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1. Effects of copy number variations on brain structure and risk for psychiatric illness: Large‐scale studies from the ENIGMA working groups on CNVs

Author

Sønderby, Ida E, Ching, Christopher RK, Thomopoulos, Sophia I, van der Meer, Dennis, Sun, Daqiang, Villalon‐Reina, Julio E, Agartz, Ingrid, Amunts, Katrin, Arango, Celso, Armstrong, Nicola J, Ayesa‐Arriola, Rosa, Bakker, Geor, Bassett, Anne S, Boomsma, Dorret I, Bülow, Robin, Butcher, Nancy J, Calhoun, Vince D, Caspers, Svenja, Chow, Eva WC, Cichon, Sven, Ciufolini, Simone, Craig, Michael C, Crespo‐Facorro, Benedicto, Cunningham, Adam C, Dale, Anders M, Dazzan, Paola, de Zubicaray, Greig I, Djurovic, Srdjan, Doherty, Joanne L, Donohoe, Gary, Draganski, Bogdan, Durdle, Courtney A, Ehrlich, Stefan, Emanuel, Beverly S, Espeseth, Thomas, Fisher, Simon E, Ge, Tian, Glahn, David C, Grabe, Hans J, Gur, Raquel E, Gutman, Boris A, Haavik, Jan, Håberg, Asta K, Hansen, Laura A, Hashimoto, Ryota, Hibar, Derrek P, Holmes, Avram J, Hottenga, Jouke‐Jan, Pol, Hilleke E Hulshoff, Jalbrzikowski, Maria, Knowles, Emma EM, Kushan, Leila, Linden, David EJ, Liu, Jingyu, Lundervold, Astri J, Martin‐Brevet, Sandra, Martínez, Kenia, Mather, Karen A, Mathias, Samuel R, McDonald‐McGinn, Donna M, McRae, Allan F, Medland, Sarah E, Moberget, Torgeir, Modenato, Claudia, Sánchez, Jennifer Monereo, Moreau, Clara A, Mühleisen, Thomas W, Paus, Tomas, Pausova, Zdenka, Prieto, Carlos, Ragothaman, Anjanibhargavi, Reinbold, Céline S, Marques, Tiago Reis, Repetto, Gabriela M, Reymond, Alexandre, Roalf, David R, Rodriguez‐Herreros, Borja, Rucker, James J, Sachdev, Perminder S, Schmitt, James E, Schofield, Peter R, Silva, Ana I, Stefansson, Hreinn, Stein, Dan J, Tamnes, Christian K, Tordesillas‐Gutiérrez, Diana, Ulfarsson, Magnus O, Vajdi, Ariana, van 't Ent, Dennis, van den Bree, Marianne BM, Vassos, Evangelos, Vázquez‐Bourgon, Javier, Vila‐Rodriguez, Fidel, Walters, G Bragi, Wen, Wei, Westlye, Lars T, Wittfeld, Katharina, Zackai, Elaine H, Stefánsson, Kári, and Jacquemont, Sebastien

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Psychology, Mental Health, Clinical Research, Pediatric, Genetics, Basic Behavioral and Social Science, Human Genome, Prevention, Brain Disorders, Behavioral and Social Science, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Mental health, Neurological, Brain, DNA Copy Number Variations, Humans, Magnetic Resonance Imaging, Mental Disorders, Multicenter Studies as Topic, Neurodevelopmental Disorders, Neuroimaging, brain structural imaging, copy number variant, diffusion tensor imaging, evolution, genetics-first approach, neurodevelopmental disorders, psychiatric disorders, ENIGMA-CNV Working Group, ENIGMA 22q11.2 Deletion Syndrome Working Group, Cognitive Sciences, Experimental Psychology, Biological psychology, Cognitive and computational psychology
Abstract

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.

Published
2022

2. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.

Author

den Hoed, Joery, de Boer, Elke, Voisin, Norine, Dingemans, Alexander, Guex, Nicolas, Wiel, Laurens, Nellaker, Christoffer, Amudhavalli, Shivarajan, Banka, Siddharth, Bena, Frederique, Ben-Zeev, Bruria, Bonagura, Vincent, Bruel, Ange-Line, Brunet, Theresa, Brunner, Han, Chew, Hui, Chrast, Jacqueline, Cimbalistienė, Loreta, Coon, Hilary, Délot, Emmanuèlle, Démurger, Florence, Denommé-Pichon, Anne-Sophie, Depienne, Christel, Donnai, Dian, Dyment, David, Elpeleg, Orly, Faivre, Laurence, Gilissen, Christian, Granger, Leslie, Haber, Benjamin, Hachiya, Yasuo, Abedi, Yasmin, Hanebeck, Jennifer, Hehir-Kwa, Jayne, Horist, Brooke, Itai, Toshiyuki, Jackson, Adam, Jewell, Rosalyn, Jones, Kelly, Joss, Shelagh, Kashii, Hirofumi, Kato, Mitsuhiro, Kattentidt-Mouravieva, Anja, Kok, Fernando, Kotzaeridou, Urania, Krishnamurthy, Vidya, Kučinskas, Vaidutis, Kuechler, Alma, Lavillaureix, Alinoë, Liu, Pengfei, Manwaring, Linda, Matsumoto, Naomichi, Mazel, Benoît, McWalter, Kirsty, Meiner, Vardiella, Mikati, Mohamad, Miyatake, Satoko, Mizuguchi, Takeshi, Moey, Lip, Mohammed, Shehla, Mor-Shaked, Hagar, Mountford, Hayley, Newbury-Ecob, Ruth, Odent, Sylvie, Orec, Laura, Osmond, Matthew, Palculict, Timothy, Parker, Michael, Petersen, Andrea, Pfundt, Rolph, Preikšaitienė, Eglė, Radtke, Kelly, Ranza, Emmanuelle, Rosenfeld, Jill, Santiago-Sim, Teresa, Schwager, Caitlin, Sinnema, Margje, Snijders Blok, Lot, Spillmann, Rebecca, Stegmann, Alexander, Thiffault, Isabelle, Tran, Linh, Vaknin-Dembinsky, Adi, Vedovato-Dos-Santos, Juliana, Schrier Vergano, Samantha, Vilain, Eric, Vitobello, Antonio, Wagner, Matias, Waheeb, Androu, Willing, Marcia, Zuccarelli, Britton, Kini, Usha, Newbury, Dianne, Kleefstra, Tjitske, Reymond, Alexandre, Fisher, Simon, and Vissers, Lisenka

Subjects
HPO-based analysis, SATB1, cell-based functional assays, de novo variants, intellectual disability, neurodevelopmental disorders, seizures, teeth abnormalities, Chromatin, Female, Genetic Association Studies, Haploinsufficiency, Humans, Male, Matrix Attachment Region Binding Proteins, Models, Molecular, Mutation, Mutation, Missense, Neurodevelopmental Disorders, Protein Binding, Protein Domains, Transcription, Genetic
Abstract

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

Published
2021

3. Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations

Author

Tripathy, Ratna, Leca, Ines, van Dijk, Tessa, Weiss, Janneke, van Bon, Bregje W, Sergaki, Maria Christina, Gstrein, Thomas, Breuss, Martin, Tian, Guoling, Bahi-Buisson, Nadia, Paciorkowski, Alexander R, Pagnamenta, Alistair T, Wenninger-Weinzierl, Andrea, Martinez-Reza, Maria Fernanda, Landler, Lukas, Lise, Stefano, Taylor, Jenny C, Terrone, Gaetano, Vitiello, Giuseppina, Del Giudice, Ennio, Brunetti-Pierri, Nicola, D’Amico, Alessandra, Reymond, Alexandre, Voisin, Norine, Bernstein, Jonathan A, Farrelly, Ellyn, Kini, Usha, Leonard, Thomas A, Valence, Stéphanie, Burglen, Lydie, Armstrong, Linlea, Hiatt, Susan M, Cooper, Gregory M, Aldinger, Kimberly A, Dobyns, William B, Mirzaa, Ghayda, Pierson, Tyler Mark, Baas, Frank, Chelly, Jamel, Cowan, Nicholas J, and Keays, David Anthony

Subjects
Biomedical and Clinical Sciences, Neurosciences, Rare Diseases, Pediatric, Genetics, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Congenital Structural Anomalies, 2.1 Biological and endogenous factors, Aetiology, Neurological, Agenesis of Corpus Callosum, Animals, Animals, Newborn, Apoptosis, Brain, Cells, Cultured, Cerebellum, Child, Developmental Disabilities, Disease Models, Animal, Embryo, Mammalian, Female, Gene Expression Regulation, Developmental, Humans, Male, Malformations of Cortical Development, Mice, Mice, Inbred C57BL, Mice, Knockout, Microtubule-Associated Proteins, Mutation, Nerve Tissue Proteins, Nervous System Malformations, PAX6 Transcription Factor, MAST1, cerebellar hypoplasia, corpus callosum, microdeletion, microtubules, Psychology, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule-associated protein that is predominantly expressed in post-mitotic neurons and is present in both dendritic and axonal compartments. We further show that Mast1 null animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In animals harboring Mast1 microdeletions, we find that the PI3K/AKT3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant-negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases.

Published
2018

4. Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility.

Author

Nuttle, Xander, Giannuzzi, Giuliana, Duyzend, Michael H, Schraiber, Joshua G, Narvaiza, Iñigo, Sudmant, Peter H, Penn, Osnat, Chiatante, Giorgia, Malig, Maika, Huddleston, John, Benner, Chris, Camponeschi, Francesca, Ciofi-Baffoni, Simone, Stessman, Holly AF, Marchetto, Maria CN, Denman, Laura, Harshman, Lana, Baker, Carl, Raja, Archana, Penewit, Kelsi, Janke, Nicolette, Tang, W Joyce, Ventura, Mario, Banci, Lucia, Antonacci, Francesca, Akey, Joshua M, Amemiya, Chris T, Gage, Fred H, Reymond, Alexandre, and Eichler, Evan E

Subjects
Chromosomes, Human, Pair 16, Animals, Humans, Pan troglodytes, Chromosome Breakage, Genetic Predisposition to Disease, Iron, Proteins, Autistic Disorder, Evolution, Molecular, Species Specificity, Gene Duplication, Recombination, Genetic, Homeostasis, Time Factors, DNA Copy Number Variations, Pongo, Human Genome, Genetics, Biotechnology, General Science & Technology
Abstract

Genetic differences that specify unique aspects of human evolution have typically been identified by comparative analyses between the genomes of humans and closely related primates, including more recently the genomes of archaic hominins. Not all regions of the genome, however, are equally amenable to such study. Recurrent copy number variation (CNV) at chromosome 16p11.2 accounts for approximately 1% of cases of autism and is mediated by a complex set of segmental duplications, many of which arose recently during human evolution. Here we reconstruct the evolutionary history of the locus and identify bolA family member 2 (BOLA2) as a gene duplicated exclusively in Homo sapiens. We estimate that a 95-kilobase-pair segment containing BOLA2 duplicated across the critical region approximately 282 thousand years ago (ka), one of the latest among a series of genomic changes that dramatically restructured the locus during hominid evolution. All humans examined carried one or more copies of the duplication, which nearly fixed early in the human lineage--a pattern unlikely to have arisen so rapidly in the absence of selection (P

Published
2016

5. Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities

Author

D’Angelo, Debra, Lebon, Sébastien, Chen, Qixuan, Martin-Brevet, Sandra, Snyder, LeeAnne Green, Hippolyte, Loyse, Hanson, Ellen, Maillard, Anne M, Faucett, W Andrew, Macé, Aurélien, Pain, Aurélie, Bernier, Raphael, Chawner, Samuel JRA, David, Albert, Andrieux, Joris, Aylward, Elizabeth, Baujat, Genevieve, Caldeira, Ines, Conus, Philippe, Ferrari, Carrina, Forzano, Francesca, Gérard, Marion, Goin-Kochel, Robin P, Grant, Ellen, Hunter, Jill V, Isidor, Bertrand, Jacquette, Aurélia, Jønch, Aia E, Keren, Boris, Lacombe, Didier, Le Caignec, Cédric, Martin, Christa Lese, Männik, Katrin, Metspalu, Andres, Mignot, Cyril, Mukherjee, Pratik, Owen, Michael J, Passeggeri, Marzia, Rooryck-Thambo, Caroline, Rosenfeld, Jill A, Spence, Sarah J, Steinman, Kyle J, Tjernagel, Jennifer, Van Haelst, Mieke, Shen, Yiping, Draganski, Bogdan, Sherr, Elliott H, Ledbetter, David H, van den Bree, Marianne BM, Beckmann, Jacques S, Spiro, John E, Reymond, Alexandre, Jacquemont, Sébastien, and Chung, Wendy K

Subjects
Biological Psychology, Psychology, Intellectual and Developmental Disabilities (IDD), Behavioral and Social Science, Mental Health, Pediatric, Clinical Research, Brain Disorders, Autism, Aetiology, 2.1 Biological and endogenous factors, Mental health, Adolescent, Adult, Autism Spectrum Disorder, Autistic Disorder, Case-Control Studies, Cerebellum, Child, Child, Preschool, Chromosome Deletion, Chromosome Disorders, Chromosome Duplication, Chromosomes, Human, Pair 16, Cognition, Cohort Studies, Comorbidity, DNA Copy Number Variations, Developmental Disabilities, Epilepsy, Female, Humans, Intellectual Disability, Male, Microcephaly, Middle Aged, Nervous System Malformations, Schizophrenia, Schizophrenic Psychology, Young Adult, Cardiff University Experiences of Children With Copy Number Variants (ECHO) Study, 16p11.2 European Consortium, Simons Variation in Individuals Project (VIP) Consortium, Other Medical and Health Sciences, Cognitive Sciences, Clinical sciences, Clinical and health psychology
Abstract

ImportanceThe 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI).ObjectivesTo characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD.Design, setting, and participantsThis international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives.Main outcomes and measuresFindings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data.ResultsAmong the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P 100) compared with the deletion group (P

Published
2016

6. Comparative analysis of the transcriptome across distant species.

Author

Gerstein, Mark B, Rozowsky, Joel, Yan, Koon-Kiu, Wang, Daifeng, Cheng, Chao, Brown, James B, Davis, Carrie A, Hillier, LaDeana, Sisu, Cristina, Li, Jingyi Jessica, Pei, Baikang, Harmanci, Arif O, Duff, Michael O, Djebali, Sarah, Alexander, Roger P, Alver, Burak H, Auerbach, Raymond, Bell, Kimberly, Bickel, Peter J, Boeck, Max E, Boley, Nathan P, Booth, Benjamin W, Cherbas, Lucy, Cherbas, Peter, Di, Chao, Dobin, Alex, Drenkow, Jorg, Ewing, Brent, Fang, Gang, Fastuca, Megan, Feingold, Elise A, Frankish, Adam, Gao, Guanjun, Good, Peter J, Guigó, Roderic, Hammonds, Ann, Harrow, Jen, Hoskins, Roger A, Howald, Cédric, Hu, Long, Huang, Haiyan, Hubbard, Tim JP, Huynh, Chau, Jha, Sonali, Kasper, Dionna, Kato, Masaomi, Kaufman, Thomas C, Kitchen, Robert R, Ladewig, Erik, Lagarde, Julien, Lai, Eric, Leng, Jing, Lu, Zhi, MacCoss, Michael, May, Gemma, McWhirter, Rebecca, Merrihew, Gennifer, Miller, David M, Mortazavi, Ali, Murad, Rabi, Oliver, Brian, Olson, Sara, Park, Peter J, Pazin, Michael J, Perrimon, Norbert, Pervouchine, Dmitri, Reinke, Valerie, Reymond, Alexandre, Robinson, Garrett, Samsonova, Anastasia, Saunders, Gary I, Schlesinger, Felix, Sethi, Anurag, Slack, Frank J, Spencer, William C, Stoiber, Marcus H, Strasbourger, Pnina, Tanzer, Andrea, Thompson, Owen A, Wan, Kenneth H, Wang, Guilin, Wang, Huaien, Watkins, Kathie L, Wen, Jiayu, Wen, Kejia, Xue, Chenghai, Yang, Li, Yip, Kevin, Zaleski, Chris, Zhang, Yan, Zheng, Henry, Brenner, Steven E, Graveley, Brenton R, Celniker, Susan E, Gingeras, Thomas R, and Waterston, Robert

Subjects
Chromatin, Animals, Humans, Drosophila melanogaster, Caenorhabditis elegans, Histones, RNA, Untranslated, Cluster Analysis, Gene Expression Profiling, Sequence Analysis, RNA, Gene Expression Regulation, Developmental, Larva, Pupa, Models, Genetic, Promoter Regions, Genetic, Molecular Sequence Annotation, Transcriptome, Genetics, Human Genome, Generic health relevance, General Science & Technology
Abstract

The transcriptome is the readout of the genome. Identifying common features in it across distant species can reveal fundamental principles. To this end, the ENCODE and modENCODE consortia have generated large amounts of matched RNA-sequencing data for human, worm and fly. Uniform processing and comprehensive annotation of these data allow comparison across metazoan phyla, extending beyond earlier within-phylum transcriptome comparisons and revealing ancient, conserved features. Specifically, we discover co-expression modules shared across animals, many of which are enriched in developmental genes. Moreover, we use expression patterns to align the stages in worm and fly development and find a novel pairing between worm embryo and fly pupae, in addition to the embryo-to-embryo and larvae-to-larvae pairings. Furthermore, we find that the extent of non-canonical, non-coding transcription is similar in each organism, per base pair. Finally, we find in all three organisms that the gene-expression levels, both coding and non-coding, can be quantitatively predicted from chromatin features at the promoter using a 'universal model' based on a single set of organism-independent parameters.

Published
2014

7. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders.

Author

Beckmann, Noam, Hanson, Ellen, Maillard, Anne, Hippolyte, Loyse, Macé, Aurélien, Ferrari, Carina, Kutalik, Zoltán, Andrieux, Joris, Aylward, Elizabeth, Barker, Mandy, Bernier, Raphael, Bouquillon, Sonia, Conus, Philippe, Delobel, Bruno, Faucett, W, Goin-Kochel, Robin, Grant, Ellen, Harewood, Louise, Hunter, Jill, Lebon, Sébastien, Ledbetter, David, Martin, Christa, Männik, Katrin, Martinet, Danielle, Ramocki, Melissa, Spence, Sarah, Steinman, Kyle, Tjernagel, Jennifer, Spiro, John, Reymond, Alexandre, Beckmann, Jacques, Chung, Wendy, Jacquemont, Sébastien, Zufferey, Flore, Mukherjee, Pratik, and Sherr, Elliott

Subjects
Adolescent, Adult, Body Mass Index, Child, Child Development Disorders, Pervasive, Chromosome Deletion, Chromosomes, Human, Pair 16, Developmental Disabilities, Female, Gene Order, Heterozygote, Humans, Intelligence Tests, Male, Phenotype, Syndrome, Young Adult
Abstract

BACKGROUND: The recurrent ~600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. OBJECTIVE: To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. METHODS: We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. RESULTS: When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. CONCLUSIONS: The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Published
2012

8. Landscape of transcription in human cells

Author

Djebali, Sarah, Davis, Carrie A, Merkel, Angelika, Dobin, Alex, Lassmann, Timo, Mortazavi, Ali, Tanzer, Andrea, Lagarde, Julien, Lin, Wei, Schlesinger, Felix, Xue, Chenghai, Marinov, Georgi K, Khatun, Jainab, Williams, Brian A, Zaleski, Chris, Rozowsky, Joel, Röder, Maik, Kokocinski, Felix, Abdelhamid, Rehab F, Alioto, Tyler, Antoshechkin, Igor, Baer, Michael T, Bar, Nadav S, Batut, Philippe, Bell, Kimberly, Bell, Ian, Chakrabortty, Sudipto, Chen, Xian, Chrast, Jacqueline, Curado, Joao, Derrien, Thomas, Drenkow, Jorg, Dumais, Erica, Dumais, Jacqueline, Duttagupta, Radha, Falconnet, Emilie, Fastuca, Meagan, Fejes-Toth, Kata, Ferreira, Pedro, Foissac, Sylvain, Fullwood, Melissa J, Gao, Hui, Gonzalez, David, Gordon, Assaf, Gunawardena, Harsha, Howald, Cedric, Jha, Sonali, Johnson, Rory, Kapranov, Philipp, King, Brandon, Kingswood, Colin, Luo, Oscar J, Park, Eddie, Persaud, Kimberly, Preall, Jonathan B, Ribeca, Paolo, Risk, Brian, Robyr, Daniel, Sammeth, Michael, Schaffer, Lorian, See, Lei-Hoon, Shahab, Atif, Skancke, Jorgen, Suzuki, Ana Maria, Takahashi, Hazuki, Tilgner, Hagen, Trout, Diane, Walters, Nathalie, Wang, Huaien, Wrobel, John, Yu, Yanbao, Ruan, Xiaoan, Hayashizaki, Yoshihide, Harrow, Jennifer, Gerstein, Mark, Hubbard, Tim, Reymond, Alexandre, Antonarakis, Stylianos E, Hannon, Gregory, Giddings, Morgan C, Ruan, Yijun, Wold, Barbara, Carninci, Piero, Guigó, Roderic, and Gingeras, Thomas R

Subjects
Genetics, Human Genome, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Alleles, Cell Line, DNA, DNA, Intergenic, Encyclopedias as Topic, Enhancer Elements, Genetic, Exons, Gene Expression Profiling, Genes, Genome, Human, Genomics, Humans, Molecular Sequence Annotation, Polyadenylation, Protein Isoforms, RNA, RNA Editing, RNA Splicing, Regulatory Sequences, Nucleic Acid, Repetitive Sequences, Nucleic Acid, Sequence Analysis, RNA, Transcription, Genetic, Transcriptome, General Science & Technology
Abstract

Eukaryotic cells make many types of primary and processed RNAs that are found either in specific subcellular compartments or throughout the cells. A complete catalogue of these RNAs is not yet available and their characteristic subcellular localizations are also poorly understood. Because RNA represents the direct output of the genetic information encoded by genomes and a significant proportion of a cell's regulatory capabilities are focused on its synthesis, processing, transport, modification and translation, the generation of such a catalogue is crucial for understanding genome function. Here we report evidence that three-quarters of the human genome is capable of being transcribed, as well as observations about the range and levels of expression, localization, processing fates, regulatory regions and modifications of almost all currently annotated and thousands of previously unannotated RNAs. These observations, taken together, prompt a redefinition of the concept of a gene.

Published
2012

10. Alpha Satellite Insertion Close to an Ancestral Centromeric Region

Author

Giannuzzi, Giuliana, Logsdon, Glennis A, Chatron, Nicolas, Miller, Danny E, Reversat, Julie, Munson, Katherine M, Hoekzema, Kendra, Bonnet-Dupeyron, Marie-Noëlle, Rollat-Farnier, Pierre-Antoine, Baker, Carl A, Sanlaville, Damien, Eichler, Evan E, Schluth-Bolard, Caroline, and Reymond, Alexandre

Subjects
Chromosomal Proteins, Non-Histone, ancestral centromere, Centromere, AcademicSubjects/SCI01130, structural variation, Humans, alpha satellite, DNA, Satellite, AcademicSubjects/SCI01180, Centromere Protein B, Discoveries, In Situ Hybridization, Fluorescence
Abstract

Human centromeres are mainly composed of alpha satellite DNA hierarchically organized as higher-order repeats (HORs). Alpha satellite dynamics is shown by sequence homogenization in centromeric arrays and by its transfer to other centromeric locations, for example, during the maturation of new centromeres. We identified during prenatal aneuploidy diagnosis by fluorescent in situ hybridization a de novo insertion of alpha satellite DNA from the centromere of chromosome 18 (D18Z1) into cytoband 15q26. Although bound by CENP-B, this locus did not acquire centromeric functionality as demonstrated by the lack of constriction and the absence of CENP-A binding. The insertion was associated with a 2.8-kbp deletion and likely occurred in the paternal germline. The site was enriched in long terminal repeats and located ∼10 Mbp from the location where a centromere was ancestrally seeded and became inactive in the common ancestor of humans and apes 20–25 million years ago. Long-read mapping to the T2T-CHM13 human genome assembly revealed that the insertion derives from a specific region of chromosome 18 centromeric 12-mer HOR array in which the monomer size follows a regular pattern. The rearrangement did not directly disrupt any gene or predicted regulatory element and did not alter the methylation status of the surrounding region, consistent with the absence of phenotypic consequences in the carrier. This case demonstrates a likely rare but new class of structural variation that we name “alpha satellite insertion.” It also expands our knowledge on alphoid DNA dynamics and conveys the possibility that alphoid arrays can relocate near vestigial centromeric sites.

Published
2021

11. Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs

Author

Sønderby, Ida E, Ching, Christopher R K, Ayesa-Arriola, Rosa, Thompson, Paul M, Bearden, Carrie E, Andreassen, Ole A, Group, ENIGMA-CNV Working, 2 Deletion Syndrome Working Group, ENIGMA 22q11., Bernard, Manon, Blackburn, Nicholas B, Bøen, Rune, de Geus, Eco, de Zwarte, Sonja M C, Bakker, Geor, Forti, Marta Di, Frei, Oleksandr, Fukunaga, Masaki, Hehir-Kwa, Jayne Y, Hillegers, Manon H J, Hoffmann, Per, Homuth, Georg, Jahanshad, Neda, Koops, Sanne, Kumar, Kuldeep, Bassett, Anne S, Kikuchi, Masataka, Le Hellard, Stephanie, Leu, Costin, Murray, Robin M, Naerland, Terje, Nyberg, Lars, Ophoff, Roel A, Pike, G Bruce, Sando, Sigrid B, Shin, Jean, Boomsma, Dorret I, Shumskaya, Elena, Sisodiya, Sanjay M, Steen, Vidar M, Teumer, Alexander, Uhlmann, Anne, Wright, Margaret J, Antshel, Kevin M, Campbell, Linda E, Crossley, Nicolas A, Crowley, T Blaine, Bülow, Robin, Daly, Eileen, Fiksinski, Ania M, Forsyth, Jennifer K, Fremont, Wanda, Goodrich-Hunsaker, Naomi J, Gudbrandsen, Maria, Jonas, Rachel K, Kates, Wendy R, Lin, Amy, McCabe, Kathryn L, Butcher, Nancy J, Moss, Hayley, Murphy, Declan G, Murphy, Kieran C, Owen, Michael J, Ruparel, Kosha, Simon, Tony J, van Amelsvoort, Therese, Vorstman, Jacob A S, Calhoun, Vince D, Caspers, Svenja, Chow, Eva W C, Cichon, Sven, Thomopoulos, Sophia I, Ciufolini, Simone, Craig, Michael C, Crespo-Facorro, Benedicto, Cunningham, Adam C, Dale, Anders M, Dazzan, Paola, de Zubicaray, Greig I, Djurovic, Srdjan, Doherty, Joanne L, Donohoe, Gary, van der Meer, Dennis, Draganski, Bogdan, Durdle, Courtney A, Ehrlich, Stefan, Emanuel, Beverly S, Espeseth, Thomas, Fisher, Simon E, Ge, Tian, Glahn, David C, Grabe, Hans J, Gur, Raquel E, Sun, Daqiang, Gutman, Boris A, Haavik, Jan, Håberg, Asta K, Hansen, Laura A, Hashimoto, Ryota, Hibar, Derrek P, Holmes, Avram J, Hottenga, Jouke-Jan, Hulshoff Pol, Hilleke E, Jalbrzikowski, Maria, Villalon-Reina, Julio E, Knowles, Emma E M, Kushan, Leila, Linden, David E J, Liu, Jingyu, Lundervold, Astri J, Martin-Brevet, Sandra, Martínez, Kenia, Mather, Karen A, Mathias, Samuel R, McDonald-McGinn, Donna M, Agartz, Ingrid, McRae, Allan F, Medland, Sarah E, Moberget, Torgeir, Modenato, Claudia, Monereo Sánchez, Jennifer, Moreau, Clara A, Mühleisen, Thomas W, Paus, Tomas, Pausova, Zdenka, Prieto, Carlos, Amunts, Katrin, Ragothaman, Anjanibhargavi, Reinbold, Céline S, Reis Marques, Tiago, Repetto, Gabriela M, Reymond, Alexandre, Roalf, David R, Rodriguez-Herreros, Borja, Rucker, James J, Sachdev, Perminder S, Schmitt, James E, Arango, Celso, Schofield, Peter R, Silva, Ana I, Stefansson, Hreinn, Stein, Dan J, Tamnes, Christian K, Tordesillas-Gutiérrez, Diana, Ulfarsson, Magnus O, Vajdi, Ariana, van 't Ent, Dennis, van den Bree, Marianne B M, Armstrong, Nicola J, Vassos, Evangelos, Vázquez-Bourgon, Javier, Vila-Rodriguez, Fidel, Walters, G Bragi, Wen, Wei, Westlye, Lars T, Wittfeld, Katharina, Zackai, Elaine H, Stefánsson, Kári, Jacquemont, Sebastien, the ENIGMA-CNV Working Group, the ENIGMA 22q11.2 Deletion Syndrome Working Group, Stochastics, Biological Psychology, APH - Mental Health, APH - Methodology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, ENIGMA-CNV Working Group, ENIGMA 22q11.2 Deletion Syndrome Working Group, and Universidad de Cantabria

Subjects
Review Article, genetics [Mental Disorders], 0302 clinical medicine, genetics-first approach, pathology [Brain], Multicenter Studies as Topic, Copy-number variation, Review Articles, education.field_of_study, brain structural imaging, Radiological and Ultrasound Technology, genetics [Neurodevelopmental Disorders], Mental Disorders, neurodevelopmental disorders, 05 social sciences, growth & development [Brain], Brain, pathology [Mental Disorders], Cognition, Human brain, diffusion tensor imaging, Magnetic Resonance Imaging, diagnostic imaging [Neurodevelopmental Disorders], medicine.anatomical_structure, psychiatric disorders, Neurology, Anatomy, medicine.medical_specialty, Brain development, DNA Copy Number Variations, Population, Neuroimaging, Biology, 050105 experimental psychology, 03 medical and health sciences, evolution, medicine, pathology [Neurodevelopmental Disorders], Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, Deletion syndrome, copy number variant, ddc:610, genetics‐first approach, education, Psychiatry, diagnostic imaging [Brain], Neurology (clinical), Working group, 030217 neurology & neurosurgery, diagnostic imaging [Mental Disorders]
Abstract

The Enhancing NeuroImaging Genetics through Meta‐Analysis copy number variant (ENIGMA‐CNV) and 22q11.2 Deletion Syndrome Working Groups (22q‐ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA‐CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q‐ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest‐ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi‐site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene‐dosage effects on distinct brain regions also emerged, providing further insight into genotype–phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This “genotype‐first” approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior., The enhancing neuroimaging genetics through meta‐analysis (ENIGMA) copy number variant (CNV) and 22q11.2 Working Groups focus on gaining insight into how rare genetic variants affect human brain development, cognition, and behavior. The two ENIGMA working groups have collated CNV and brain‐imaging data from numerous individuals, gathered by numerous international research centers, and analyzed this data with standardized processing and analysis pipelines. Future directions for the ENIGMA CNV and 22q11.2 working groups are to analyze CNVs with larger sample sizes and more imaging modalities to better understand how rare genetic variants affect the brain, and their clinical and behavioral consequences.

Published
2021

12. Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution

Author

Hillier, LaDeana W, Miller, Webb, Birney, Ewan, Warren, Wesley, Hardison, Ross C, Ponting, Chris P, Bork, Peer, Burt, Peer, Groenen, Martien A M, Delany, Mary E, Dodgson, Jerry B, Chinwalla, Asif, Cliften, Paul F, Clifton, Sandra W, Delehaunty, Kimberly D, Fronick, Catrina, Fulton, Robert S, Graves, Tina A, Kremitzki, Colin, Layman, Dan, Magrini, Vincent, McPherson, John D, Miner, Tracie L, Minx, Patrick, Nash, William E, Nhan, Michael N, Nelson, Joanne O, Oddy, Lachlan G, Pohl, Craig S, Randall-Maher, Jennifer, Smith, Scott M, Wallis, John W, Yang, Shiaw-Pyng, Romanov, Michael N, Rondelli, Catherine M, Paton, Bob, Smith, Jacqueline, Morrice, David, Daniels, Laura, Tempest, Helen G, Robertson, Lindsay, Masabanda, Julio S, Griffin, Darren K., Vignal, Alain, Fillon, Valerie, Jacobbson, Lina, Kerje, Susanne, Andersson, Leif, Crooijmans, Richard P M A, Aerts, Jan, van der Poel, Jan J, Ellegren, Hans, Caldwell, Randolph B, Hubbard, Simon J, Grafham, Darren V, Kierzek, Andrzej M, McLaren, Stuart R, Overton, Ian M, Arakawa, Hiroshi, Beattie, Kevin J, Bezzubov, Yuri, Boardman, Paul E, Bonfield, James K, Croning, Michael D R, Davies, Robert M, Francis, Matthew D, Humphray, Sean J, Scott, Carol E, Taylor, Ruth G, Tickle, Cheryll, Brown, William R A, Rogers, Jane, Buerstedde, Jean-Marie, Wilson, Stuart A, Stubbs, Lisa, Ovcharenko, Ivan, Gordon, Laurie, Lucas, Susan, Miller, Marcia M, Inoko, Hidetoshi, Shiina, Takashi, Kaufman, Jim, Salomonsen, Jan, Skjoedt, Karsten, Wong, Gane Ka-Shu, Wang, Jun, Liu, Bin, Wang, Jian, Yu, Jun, Yang, Huanming, Nefedov, Mikhail, Koriabine, Maxim, de Jong, Pieter J, Goodstadt, Leo, Webber, Caleb, Dickens, Nicholas J, Letunic, Ivica, Suyama, Mikita, Torrents, David, von Mering, Christian, Zdobnov, Evgeny M, Makova, Kateryna, Nekrutenko, Anton, Elnitski, Laura, Eswara, Pallavi, King, David C, Yang, Shan, Tyekucheva, Svitlana, Radakrishnan, Anusha, Harris, Robert S, Chiaromonte, Francesca, Taylor, James, He, Jianbin, Rijnkels, Monique, Griffiths-Jones, Sam, Ureta-Vidal, Abe, Hoffman, Michael M, Severin, Jessica, Searle, Stephen M J, Law, Andy S, Speed, David, Waddington, David, Cheng, Ze, Tuzun, Eray, Eichler, Evan, Bao, Zhirong, Flicek, Paul, Shteynberg, David D, Brent, Michael R, Bye, Jacqueline M, Huckle, Elizabeth J, Chatterjee, Sourav, Dewey, Colin, Pachter, Lior, Kouranov, Andrei, Mourelatos, Zissimos, Hatzigeorgiou, Artemis G, Paterson, Andrew H, Ivarie, Robert, Brandstrom, Mikael, Axelsson, Erik, Backström, Niclas, Berlin, Sofia, Webster, Matthew T, Pourquie, Olivier, Reymond, Alexandre, Ucla, Catherine, Antonarakis, Stylianos E, Long, Manyuan, Emerson, J J, Betran, Esther, Dupanloup, Isabelle, Kaessmann, Henrik, Hinrichs, Angie S, Bejerano, Gill, Furey, Terrence S, Harte, Rachel A, Raney, Brian, Siepel, Adam, Kent, W James, Haussler, David, Eyras, Eduardo, Castelo, Robert, Abril, Josep F, Castellano, Sergi, Camara, Francisco, Parra, Genis, Guigo, Roderic, Bourque, Guillaume, Tesler, Glenn, Pevzner, Pavel A., Smit, Arian F. A., Fulton, Lucinda A., Mardis, Elaine R., Wilson, Richard K., International Chicken Genome Sequencing Consortium, ProdInra, Migration, Laboratoire de Génétique Cellulaire (LGC), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Zdobnov, Evgeny

Subjects
RNA, Untranslated, olfactory receptor, [SDV]Life Sciences [q-bio], mouse genome, QH75, Genome, 0302 clinical medicine, Gene Duplication, Coding region, ddc:576.5, Conserved Sequence, ComputingMilieux_MISCELLANEOUS, Short Interspersed Nucleotide Elements, Genetics, 0303 health sciences, Multidisciplinary, CHICKENS, recent segmental duplications, Untranslated, GENOME SEQUENCE, International Chicken Genome Sequencing Consortium, Genomics, Physical Chromosome Mapping, major histocompatibility complex, mammalian evolution, [SDV] Life Sciences [q-bio], Multigene Family, Vertebrates, SEQUENCE DU GENOME, Sequence Analysis, Pseudogenes, Biotechnology, brown-norway rat, animal structures, Evolution, General Science & Technology, Sequence analysis, Biology, Animal Breeding and Genomics, Synteny, Evolution, Molecular, Avian Proteins, 03 medical and health sciences, non-ltr retrotransposons, Animals, Humans, alcohol-dehydrogenase, Fokkerij en Genomica, SF, QP506, Gene, QH426, 030304 developmental biology, Whole genome sequencing, QL, phylogenetic analysis, QH, Human Genome, Molecular, Sequence Analysis, DNA, DNA, tissue-specific genes, EVOLUTION, Retroviridae, Long Interspersed Nucleotide Elements, Genes, Mutagenesis, Evolutionary biology, DNA Transposable Elements, Microchromosome, WIAS, RNA, Chickens, 030217 neurology & neurosurgery
Abstract

We present here a draft genome sequence of the red jungle fowl, Gallus gallus. Because the chicken is a modern descendant of the dinosaurs and the first non-mammalian amniote to have its genome sequenced, the draft sequence of its genome--composed of approximately one billion base pairs of sequence and an estimated 20,000-23,000 genes--provides a new perspective on vertebrate genome evolution, while also improving the annotation of mammalian genomes. For example, the evolutionary distance between chicken and human provides high specificity in detecting functional elements, both non-coding and coding. Notably, many conserved non-coding sequences are far from genes and cannot be assigned to defined functional classes. In coding regions the evolutionary dynamics of protein domains and orthologous groups illustrate processes that distinguish the lineages leading to birds and mammals. The distinctive properties of avian microchromosomes, together with the inferred patterns of conserved synteny, provide additional insights into vertebrate chromosome architecture.

Published
2004

13. Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics

Author

Loviglio, Maria Nicla, Beck, Christine R., White, Janson J., Leleu, Marion, Harel, Tamar, Guex, Nicolas, Niknejad, Anne, Bi, Weimin, Chen, Edward S., Crespo, Isaac, Yan, Jiong, Charng, Wu-Lin, Gu, Shen, Fang, Ping, Coban-Akdemir, Zeynep, Shaw, Chad A., Jhangiani, Shalini N., Muzny, Donna M., Gibbs, Richard A., Rougemont, Jacques, Xenarios, Ioannis, Lupski, James R., and Reymond, Alexandre

Subjects
Male, Text mining, lcsh:QH426-470, Intellectual disability, lcsh:Medicine, Real-Time Polymerase Chain Reaction, Disease network, Mice, Genetics, Animals, Humans, Exome, Gene Regulatory Networks, Chromatin conformation, Diagnostic, Genetics(clinical), RNA, Messenger, Molecular Biology, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Research, lcsh:R, Genomics, Embryo, Mammalian, Mice, Inbred C57BL, lcsh:Genetics, Phenotype, Mutation, Trans-Activators, Molecular Medicine, Female, Smith-Magenis Syndrome, Transcriptome, Transcription Factors
Abstract

Background Smith-Magenis syndrome (SMS) is a developmental disability/multiple congenital anomaly disorder resulting from haploinsufficiency of RAI1. It is characterized by distinctive facial features, brachydactyly, sleep disturbances, and stereotypic behaviors. Methods We investigated a cohort of 15 individuals with a clinical suspicion of SMS who showed neither deletion in the SMS critical region nor damaging variants in RAI1 using whole exome sequencing. A combination of network analysis (co-expression and biomedical text mining), transcriptomics, and circularized chromatin conformation capture (4C-seq) was applied to verify whether modified genes are part of the same disease network as known SMS-causing genes. Results Potentially deleterious variants were identified in nine of these individuals using whole-exome sequencing. Eight of these changes affect KMT2D, ZEB2, MAP2K2, GLDC, CASK, MECP2, KDM5C, and POGZ, known to be associated with Kabuki syndrome 1, Mowat-Wilson syndrome, cardiofaciocutaneous syndrome, glycine encephalopathy, mental retardation and microcephaly with pontine and cerebellar hypoplasia, X-linked mental retardation 13, X-linked mental retardation Claes-Jensen type, and White-Sutton syndrome, respectively. The ninth individual carries a de novo variant in JAKMIP1, a regulator of neuronal translation that was recently found deleted in a patient with autism spectrum disorder. Analyses of co-expression and biomedical text mining suggest that these pathologies and SMS are part of the same disease network. Further support for this hypothesis was obtained from transcriptome profiling that showed that the expression levels of both Zeb2 and Map2k2 are perturbed in Rai1 –/– mice. As an orthogonal approach to potentially contributory disease gene variants, we used chromatin conformation capture to reveal chromatin contacts between RAI1 and the loci flanking ZEB2 and GLDC, as well as between RAI1 and human orthologs of the genes that show perturbed expression in our Rai1 –/– mouse model. Conclusions These holistic studies of RAI1 and its interactions allow insights into SMS and other disorders associated with intellectual disability and behavioral abnormalities. Our findings support a pan-genomic approach to the molecular diagnosis of a distinctive disorder. Electronic supplementary material The online version of this article (doi:10.1186/s13073-016-0359-z) contains supplementary material, which is available to authorized users.

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14. Secondary structure of the human mitochondrial genome affects formation of deletions

Author

Victor Shamanskiy, Alina A. Mikhailova, Evgenii O. Tretiakov, Kristina Ushakova, Alina G. Mikhailova, Sergei Oreshkov, Dmitry A. Knorre, Natalia Ree, Jonathan B. Overdevest, Samuel W. Lukowski, Irina Gostimskaya, Valerian Yurov, Chia-Wei Liou, Tsu-Kung Lin, Wolfram S. Kunz, Alexandre Reymond, Ilya Mazunin, Georgii A. Bazykin, Jacques Fellay, Masashi Tanaka, Konstantin Khrapko, Konstantin Gunbin, Konstantin Popadin, Shamanskiy, Victor [0000-0001-7722-2232], Mikhailova, Alina A [0000-0002-6203-9977], Tretiakov, Evgenii O [0000-0001-5920-2190], Ushakova, Kristina [0000-0002-6461-7777], Mikhailova, Alina G [0000-0002-5494-3536], Oreshkov, Sergei [0000-0003-2030-5605], Knorre, Dmitry A [0000-0001-7468-6963], Overdevest, Jonathan B [0000-0002-1152-2512], Lukowski, Samuel W [0000-0002-8598-7902], Liou, Chia-Wei [0000-0002-9003-4065], Lin, Tsu-Kung [0000-0001-6656-1319], Kunz, Wolfram S [0000-0003-1113-3493], Reymond, Alexandre [0000-0003-1030-8327], Mazunin, Ilya [0000-0002-5448-9679], Bazykin, Georgii A [0000-0003-2334-2751], Fellay, Jacques [0000-0002-8240-939X], Khrapko, Konstantin [0000-0002-9250-8033], Gunbin, Konstantin [0000-0003-1851-8169], Popadin, Konstantin [0000-0002-2117-6086], and Apollo - University of Cambridge Repository

Subjects
Aging, Contact zone, Physiology, Inverted repeats, DNA, Single-Stranded, clonal expansion, Plant Science, dna deletions, system, DNA, Mitochondrial, Protein Structure, Secondary, General Biochemistry, Genetics and Molecular Biology, Structural Biology, Animals, Humans, Deletions, Ecology, Evolution, Behavior and Systematics, life-span, Mammals, human oocytes, Genome, Human, Cell Biology, organization, sequence, Global secondary structure, mutations, Mitochondrial DNA, mtDNA replication, Mitochondria, Genome, Mitochondrial, accumulation, General Agricultural and Biological Sciences, Direct repeats, Single-stranded DNA, Developmental Biology, Biotechnology
Abstract

Background Aging in postmitotic tissues is associated with clonal expansion of somatic mitochondrial deletions, the origin of which is not well understood. Such deletions are often flanked by direct nucleotide repeats, but this alone does not fully explain their distribution. Here, we hypothesized that the close proximity of direct repeats on single-stranded mitochondrial DNA (mtDNA) might play a role in the formation of deletions. Results By analyzing human mtDNA deletions in the major arc of mtDNA, which is single-stranded during replication and is characterized by a high number of deletions, we found a non-uniform distribution with a “hot spot” where one deletion breakpoint occurred within the region of 6–9 kb and another within 13–16 kb of the mtDNA. This distribution was not explained by the presence of direct repeats, suggesting that other factors, such as the spatial proximity of these two regions, can be the cause. In silico analyses revealed that the single-stranded major arc may be organized as a large-scale hairpin-like loop with a center close to 11 kb and contacting regions between 6–9 kb and 13–16 kb, which would explain the high deletion activity in this contact zone. The direct repeats located within the contact zone, such as the well-known common repeat with a first arm at 8470–8482 bp (base pair) and a second arm at 13,447–13,459 bp, are three times more likely to cause deletions compared to direct repeats located outside of the contact zone. A comparison of age- and disease-associated deletions demonstrated that the contact zone plays a crucial role in explaining the age-associated deletions, emphasizing its importance in the rate of healthy aging. Conclusions Overall, we provide topological insights into the mechanism of age-associated deletion formation in human mtDNA, which could be used to predict somatic deletion burden and maximum lifespan in different human haplogroups and mammalian species.

Published
2023

15. Variants in USP48 encoding ubiquitin hydrolase are associated with autosomal dominant non-syndromic hereditary hearing loss

Author

Alexandre Reymond, Paolo Gasparini, Jacqueline Chrast, Hannie Kremer, Sissy Bassani, Giorgia Girotto, Jiddeke M. van de Kamp, Massimiliano Cocca, Nicolas Guex, Benjamin Delprat, Mireille Rossel, Francesca Amati, Flavio Faletra, Heiko Locher, Yoan Arribat, Sylvain Pradervand, Alban Ziegler, Jeroen Smits, Sandrine Marlin, Norine Voisin, Giuliana Giannuzzi, Tangui Maurice, Anna Morgan, Roxane Machavoine, Edward S A van Beelen, Nicolas Chatron, Clinical genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Gastroenterology Endocrinology Metabolism, Bassani, Sissy, van Beelen, Edward, Rossel, Mireille, Voisin, Norine, Morgan, Anna, Arribat, Yoan, Chatron, Nicola, Chrast, Jacqueline, Cocca, Massimiliano, Delprat, Benjamin, Faletra, Flavio, Giannuzzi, Giuliana, Guex, Nicola, Machavoine, Roxane, Pradervand, Sylvain, Smits, Jeroen J, van de Kamp, Jiddeke M, Ziegler, Alban, Amati, Francesca, Marlin, Sandrine, Kremer, Hannie, Locher, Heiko, Maurice, Tangui, Gasparini, Paolo, Girotto, Giorgia, and Reymond, Alexandre

Subjects
0301 basic medicine, Reflex, Startle, Hydrolases, Hearing loss, Spiral limbus, ubiquitin hydrolase, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Hereditary hearing loss, USP48, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, otorhinolaryngologic diseases, Animals, Humans, Missense mutation, Inner ear, Hearing Loss, Molecular Biology, Zebrafish, Genetics (clinical), Exome sequencing, Spiral ganglion, biology, Ubiquitin, Cochlear nerve, Hereditary hearing lo, General Medicine, biology.organism_classification, 030104 developmental biology, medicine.anatomical_structure, Ubiquitin-Specific Proteases, sense organs, medicine.symptom, 030217 neurology & neurosurgery
Abstract

Non-Syndromic Hereditary Hearing Loss (NSHHL) is a genetically heterogeneous sensory disorder with about 120 genes already associated. Through exome sequencing (ES) and data aggregation, we identified a family with six affected individuals and one unrelated NSHHL patient with predicted-to-be deleterious missense variants in USP48. We also uncovered an eighth patient presenting unilateral cochlear nerve aplasia and a de novo splice variant in the same gene. USP48 encodes a ubiquitin carboxyl-terminal hydrolase under evolutionary constraint. Pathogenicity of the variants is supported by in vitro assays that showed that the mutated proteins are unable to hydrolyze tetra-ubiquitin. Correspondingly, three-dimensional representation of the protein containing the familial missense variant is situated in a loop that might influence the binding to ubiquitin. Consistent with a contribution of USP48 to auditory function, immunohistology showed that the encoded protein is expressed in the developing human inner ear, specifically in the spiral ganglion neurons, outer sulcus, interdental cells of the spiral limbus, stria vascularis, Reissner's membrane and in the transient Kolliker's organ that is essential for auditory development. Engineered zebrafish knocked-down for usp48, the USP48 ortholog, presented with a delayed development of primary motor neurons, less developed statoacoustic neurons innervating the ears, decreased swimming velocity and circling swimming behavior indicative of vestibular dysfunction and hearing impairment. Corroboratingly, acoustic startle response assays revealed a significant decrease of auditory response of zebrafish lacking usp48 at 600 and 800 Hz wavelengths. In conclusion, we describe a novel autosomal dominant NSHHL gene through a multipronged approach combining ES, animal modeling, immunohistology and molecular assays. influence the binding to ubiquitin. Consistent with a contribution of USP48 to auditory function, immunohistology showed that the encoded protein is expressed in the developing human inner ear, specifically in the spiral ganglion neurons, outer sulcus, interdental cells of the spiral limbus, stria vascularis, Reissner’s membrane and in the transient Kolliker’s organ that is essential for auditory development. Engineered zebrafish knocked-down for usp48, the USP48 ortholog, presented with a delayed development of primary motor neurons, less developed statoacoustic neurons innervating the ears, decreased swimming velocity and circling swimming behavior indicative of vestibular dysfunction and hearing impairment. Corroboratingly, acoustic startle response assays revealed a significant decrease of auditory response of zebrafish lacking usp48 at 600 and 800 Hz wavelengths. In conclusion, we describe a novel autosomal dominant NSHHL gene through a multipronged approach combining ES, animal modeling, immunohistology and molecular assays.

Published
2021

16. Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations

Author

William B. Dobyns, Maria Fernanda Martinez-Reza, Jamel Chelly, Tessa van Dijk, Lydie Burglen, Martin W. Breuss, Gregory M. Cooper, Stefano Lise, Nadia Bahi-Buisson, Norine Voisin, Usha Kini, Linlea Armstrong, Nicholas J. Cowan, Stéphanie Valence, Andrea Wenninger-Weinzierl, Thomas A. Leonard, Frank Baas, Lukas Landler, Ennio Del Giudice, Jonathan A. Bernstein, Ghayda Mirzaa, Guoling Tian, Kimberly A. Aldinger, Bregje W.M. van Bon, Alexandre Reymond, Tyler Mark Pierson, Giuseppina Vitiello, Ratna Tripathy, Thomas Gstrein, Gaetano Terrone, Alex R. Paciorkowski, Maria Christina Sergaki, Alessandra D'Amico, Susan M. Hiatt, Ines Leca, Janneke Weiss, Ellyn Farrelly, Alistair T. Pagnamenta, Jenny C. Taylor, Nicola Brunetti-Pierri, David A. Keays, Tripathy, Ratna, Leca, Ine, van Dijk, Tessa, Weiss, Janneke, van Bon, Bregje W, Sergaki, Maria Christina, Gstrein, Thoma, Breuss, Martin, Tian, Guoling, Bahi-Buisson, Nadia, Paciorkowski, Alexander R, Pagnamenta, Alistair T, Wenninger-Weinzierl, Andrea, Martinez-Reza, Maria Fernanda, Landler, Luka, DE LISE, Stefano, Taylor, Jenny C, Terrone, Gaetano, Vitiello, Giuseppina, Del Giudice, Ennio, Brunetti-Pierri, Nicola, D'Amico, Alessandra, Reymond, Alexandre, Voisin, Norine, Bernstein, Jonathan A, Farrelly, Ellyn, Kini, Usha, Leonard, Thomas A, Valence, Stéphanie, Burglen, Lydie, Armstrong, Linlea, Hiatt, Susan M, Cooper, Gregory M, Aldinger, Kimberly A, Dobyns, William B, Mirzaa, Ghayda, Pierson, Tyler Mark, Baas, Frank, Chelly, Jamel, Cowan, Nicholas J, and Keays, David Anthony

Subjects
0301 basic medicine, Male, Microcephaly, Pathology, PAX6 Transcription Factor, Developmental Disabilities, Apoptosis, Corpus callosum, Inbred C57BL, AKT3, corpus callosum, Mice, Cerebellum, 2.1 Biological and endogenous factors, Psychology, Developmental, Megalencephaly, Aetiology, Child, Cells, Cultured, Mice, Knockout, Pediatric, Cultured, General Neuroscience, Gene Expression Regulation, Developmental, Brain, Phenotype, Malformations of Cortical Development, Embryo, Neurological, Female, MAST1, Cognitive Sciences, Microtubule-Associated Proteins, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], medicine.medical_specialty, cerebellar hypoplasia, Cells, Knockout, Intellectual and Developmental Disabilities (IDD), Nerve Tissue Proteins, Biology, Nervous System Malformations, Article, microtubules, 03 medical and health sciences, Rare Diseases, All institutes and research themes of the Radboud University Medical Center, medicine, Genetics, Animals, Humans, PI3K/AKT/mTOR pathway, Neurology & Neurosurgery, Animal, Mammalian, Neurosciences, medicine.disease, Embryo, Mammalian, Newborn, Brain Disorders, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Animals, Newborn, Gene Expression Regulation, Disease Models, Mutation, Autism, Congenital Structural Anomalies, Cerebellar hypoplasia (non-human), Agenesis of Corpus Callosum, microdeletion
Abstract

Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule associated protein, that is predominantly expressed in post-mitotic neurons, and is present in both dendritic and axonal compartments. We further show that Mast1 null animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In animals harboring Mast1 microdeletions we find that the PI3K/AKT3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases.

Published
2018

17. De novo PIK3R2 variant causes polymicrogyria, corpus callosum hyperplasia and focal cortical dysplasia

Author

Giuseppina Vitiello, A. James Barkovich, Alexandre Reymond, Gaetano Terrone, Nicola Brunetti-Pierri, Nicolas Guex, Ennio Del Giudice, Alessandra D'Amico, Gerarda Cappuccio, Ali Abdullah Alfaiz, Norine Voisin, Terrone, Gaetano, Voisin, Norine, Abdullah Alfaiz, Ali, Cappuccio, Gerarda, Vitiello, Giuseppina, Guex, Nicola, D’Amico, Alessandra, James Barkovich, A., BRUNETTI PIERRI, Nicola, DEL GIUDICE, Ennio, and Reymond, Alexandre

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Pathology, Short Report, Mutation, Missense, Biology, Corpus callosum, 03 medical and health sciences, Phosphatidylinositol 3-Kinases, Genetic linkage, medicine, Polymicrogyria, Genetics, Humans, Megalencephaly, Child, Genetics (clinical), Cytogenetics, Syndrome, Cortical dysplasia, Perisylvian polymicrogyria, medicine.disease, Malformations of Cortical Development, 030104 developmental biology, Phenotype, Medical genetics, Agenesis of Corpus Callosum
Abstract

We report an 8-year-old boy with a complex cerebral malformation, intellectual disability, and complex partial seizures. Whole-exome sequencing revealed a yet unreported de novo variant in the PIK3R2 gene that was recently associated with megalencephaly–polymicrogyria–polydactyly–hydrocephalus (MPPH) syndrome and bilateral perisylvian polymicrogyria (BPP). Our patient showed cerebral abnormalities (megalencephaly, perisylvian polymicrogyria, and mega corpus callosum) that were consistent with these conditions. Imaging also showed right temporal anomalies suggestive of cortical dysplasia. Until now, only three variants (c.1117G>A (p.(G373R)), c.1126A>G (p.(K376E)) and c.1202T>C (p.(L401P))) affecting the SH2 domain of the PIK3R2 protein have been reported in MPPH and BPP syndromes. In contrast to the variants reported so far, the patient described herein exhibits the c.1669G>C (p.(D557H)) variant that affects a highly conserved residue at the interface with the PI3K catalytic subunit α. The phenotypic spectrum associated with variants in this gene and its pathway are likely to continue to expand as more cases are identified.European Journal of Human Genetics advance online publication, 10 February 2016; doi:10.1038/ejhg.2016.7. © 2016 Macmillan Publishers Limited

Published
2016

18. GNB5 Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability

Author

Alexandre Reymond, Carolina Fischinger Moura de Souza, Pasquelena De Nittis, James R. Lupski, Zeynep Coban Akdemir, Mohammad K. Eldomery, Teun P. de Boer, Wim de Graaff, Giuseppe Merla, Elisabeth M. Lodder, Connie R. Bezzina, William F. Simonds, Nicolas Guex, Najim Lahrouchi, Federico Tessadori, Valerio Napolioni, Jeroen Bakkers, Eline A. Nannenberg, Maarten Kamermans, Charlotte D. Koopman, Richard J. Fish, Lamiae Boualla, Barbara Mandriani, Nico A. Blom, Marguerite Neerman-Arbez, Wojciech Wiszniewski, Leander Beekman, V. Reid Sutton, Ilham Ratbi, Arthur A.M. Wilde, Fernando Kok, Dario Cocciadiferro, Natascia Malerba, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Graduate School, Human Genetics, Paediatric Cardiology, ANS - Cellular & Molecular Mechanisms, Hubrecht Institute for Developmental Biology and Stem Cell Research, Netherlands Institute for Neuroscience (NIN), Fish, Richard, Neerman Arbez, Marguerite, Reymond, Alexandre, and Merla, Giuseppe

Subjects
Male, 0301 basic medicine, Pediatrics, Muscle Hypotonia, Developmental Disabilities, Sinus bradycardia, G-protein signaling, Intellectual disability, Disease, Bioinformatics, Cognitive disabilities, Missense mutation, Medicine, ddc:576.5, Genetics(clinical), Child, Exome sequencing, Zebrafish, Genetics (clinical), Sinoatrial Node, Genetics, GTP-Binding Protein beta Subunits, Syndrome, Hypotonia, Pedigree, 3. Good health, Phenotype, Whole-exome sequencing, Gastroesophageal Reflux, Female, medicine.symptom, Bradycardia, Heterozygote, medicine.medical_specialty, Parasympathetic system, Adolescent, Heart rate, Mutation, Missense, Genes, Recessive, Young Adult, 03 medical and health sciences, Retinal Diseases, Seizures, Report, Journal Article, Animals, Humans, business.industry, Correction, Zebrafish Proteins, medicine.disease, Human genetics, 030104 developmental biology, Mutation, business, Gene Deletion
Abstract

GNB5 encodes the G protein β subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in . GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal reflux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish . gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision.

Published
2016

19. Rox, a novel bHLHZip protein expressed in quiescent cells that heterodimerizes with Max, binds a non-canonical E box and acts as a transcriptional repressor

Author

Rossana Tonlorenzi, Alexandre Reymond, Massimo Zollo, David H. Ledbetter, Myriam Alcalay, Andrea Ballabio, Cristiana Lo Nigro, Romeo Carrozzo, Silvia Messali, Giuseppe Borsani, Germana Meroni, Akira Tanigami, Roger Brent, Meroni, Germana, Reymond, Alexandre, Alcalay, Miriam, Borsani, Giuseppe, Tanigami, Akira, Tonlorenzi, Rossana, Lonigro, Cristiana, Messali, Silvia, Zollo, Massimo, Ledbetter, David H, Brent, Roger, Ballabio, Andrea, and Carrozzo, Romeo

Subjects
Leucine zipper, Saccharomyces cerevisiae Proteins, Transcription, Genetic, Cellular differentiation, Molecular Sequence Data, Repressor, E-box, Myc, Biology, DNA-binding protein, transcriptional repressor, Histone Deacetylases, General Biochemistry, Genetics and Molecular Biology, Proto-Oncogene Proteins c-myc, Mice, Animals, Humans, Amino Acid Sequence, Cloning, Molecular, Molecular Biology, Transcription factor, Regulation of gene expression, Leucine Zippers, Binding Sites, sin3, Sequence Homology, Amino Acid, General Immunology and Microbiology, Basic helix-loop-helix, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, General Neuroscience, Helix-Loop-Helix Motifs, Chromosome Mapping, Nuclear Proteins, Molecular biology, DNA-Binding Proteins, Repressor Proteins, bHLHZip proteins, Basic-Leucine Zipper Transcription Factors, Max‐interacting proteins, Gene Expression Regulation, bHLHZip proteins, Max‐interacting proteins, Myc, sin3, transcriptional repressor, Dimerization, Research Article, Chromosomes, Human, Pair 17, Protein Binding, Transcription Factors
Abstract

Proteins of the Myc and Mad family are involved in transcriptional regulation and mediate cell differentiation and proliferation. These molecules share a basic-helix-loop-helix leucine zipper domain (bHLHZip) and bind DNA at the E box (CANNTG) consensus by forming heterodimers with Max. We report the isolation, characterization and mapping of a human gene and its mouse homolog encoding a new member of this family of proteins, named Rox. Through interaction mating and immunoprecipitation techniques, we demonstrate that Rox heterodimerizes with Max and weakly homodimerizes. Interestingly, bandshift assays demonstrate that the Rox-Max heterodimer shows a novel DNA binding specificity, having a higher affinity for the CACGCG site compared with the canonical E box CACGTG site. Transcriptional studies indicate that Rox represses transcription in both human HEK293 cells and yeast. We demonstrate that repression in yeast is through interaction between the N-terminus of the protein and the Sin3 co-repressor, as previously shown for the other Mad family members. ROX is highly expressed in quiescent fibroblasts and expression markedly decreases when cells enter the cell cycle. Moreover, ROX expression appears to be induced in U937 myeloid leukemia cells stimulated to differentiate with 12-O-tetradecanoylphorbol-13-acetate. The identification of a novel Max-interacting protein adds an important piece to the puzzle of Myc/Max/Mad coordinated action and function in normal and pathological situations. Furthermore, mapping of the human gene to chromosome 17p13.3 in a region that frequently undergoes loss of heterozygosity in a number of malignancies, together with the biochemical and expression features, suggest involvement of ROX in human neoplasia.

Published
1997

20. Evidence for Transcript Networks Composed of Chimeric RNAs in Human Cells

Author

Vincent Lacroix, Sylvain Foissac, Ryan R. Murray, Sarah Djebali, Cédric Howald, Josep Lluís Gelpí, Paolo Ribeca, Alexandre Reymond, Kourosh Salehi-Ashtiani, Marc Vidal, Roderic Guigó, Thomas R. Gingeras, John A. Stamatoyannopoulos, Erica Dumais, Alexander Dobin, Bryan R. Lajoie, Tim Hubbard, Stylianos E. Antonarakis, Catherine Ucla, Ian Bell, Jacqueline Chrast, Alfonso Valencia, Modesto Orozco, Philippe Batut, Christelle Borel, Adam Frankish, Philipp Kapranov, Jorg Drenkow, Michael L. Tress, Chenwei Lin, Jennifer Harrow, Xinping Yang, Lila Ghamsari, Job Dekker, David C. Martin, Jonathan M. Mudge, Julien Lagarde, Nynke L. van Berkum, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Universitat Pompeu Fabra [Barcelona] (UPF), Affymetrix Inc., Geneva University Hospital (HUG), The Wellcome Trust Sanger Institute [Cambridge], Laboratoire de Génétique Cellulaire (LGC), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université de Lausanne (UNIL), Dana-Farber Cancer Institute [Boston], Harvard University [Cambridge], Cold Spring Harbor Laboratory, Spanish National Cancer Research Centre, University of Barcelona, Sagot, Marie-France, Universitat de Barcelona, Centro de Regulación Genómica (CRG), Affymetrix, An algorithmic view on genomes, cells, and environments (BAMBOO), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Université de Genève (UNIGE), Sanger Institute, Wellcome Trust, Harvard Medical School [Boston] (HMS), Cold Spring Harbor Laboratory (CSHL), Spanish National Cancer Research Center (CNIO), Universitat de Barcelona (UB), University of Massachusetts [Amherst] (UMass Amherst), University of Massachusetts System (UMASS), University of Washington [Seattle], Universitat Pompeu Fabra [Barcelona], Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT), Université de Lausanne = University of Lausanne (UNIL), Harvard University, Université de Genève = University of Geneva (UNIGE), Borel, Christelle, Ucla, Catherine, Martin, David, Reymond, Alexandre, and Antonarakis, Stylianos

Subjects
Male, Transcription, Genetic, Microarrays, [SDV]Life Sciences [q-bio], Gene Identification and Analysis, lcsh:Medicine, Gene Expression, Validation Studies as Topic, Transcriptomes, Exon, Transcriptome/physiology, 0302 clinical medicine, Transcripció genètica, Gene Regulatory Networks/genetics/physiology, RNA Isoforms, Gene expression, Molecular Cell Biology, site, ddc:576.5, Cells/metabolism, Gene Regulatory Networks, Molecular genetics, Nucleic Acid Amplification Techniques/methods, lcsh:Science, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], Genetics, 0303 health sciences, Multidisciplinary, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Genetic transcription, element, Statistics, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], tool, Genomics, reverse transcription, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, encode, Chromosomes, Human, Pair 1/genetics, annotation, Chromosomes, Human, Pair 1, RNA/genetics/physiology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Sequence Analysis, Nucleic Acid Amplification Techniques, Algorithms, Research Article, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], Cells, cloning, Chimerin Proteins/chemistry/genetics, Chimeric gene, Biology, Metabolisme cel·lular, Biostatistics, Models, Biological, Genètica molecular, Molecular Genetics, 03 medical and health sciences, Genome Analysis Tools, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], human genome, Chimerin Proteins/chemistry, Chimerin Proteins/genetics, Gene Expression Profiling, Gene Regulatory Networks/genetics, Gene Regulatory Networks/physiology, Humans, Microarray Analysis/methods, RNA/genetics, RNA/physiology, RNA Isoforms/chemistry, RNA Isoforms/genetics, Transcription, Genetic/genetics, Gene, 030304 developmental biology, RNA Isoforms/chemistry/genetics/metabolism, [SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT], lcsh:R, Chimerin Proteins, RNA, gene fusion, Computational Biology, Microarray Analysis, Gene expression profiling, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Human genome, lcsh:Q, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], discovery, Genome Expression Analysis, Transcriptome, 030217 neurology & neurosurgery, Genètica, Mathematics
Abstract

The classic organization of a gene structure has followed the Jacob and Monod bacterial gene model proposed more than 50 years ago. Since then, empirical determinations of the complexity of the transcriptomes found in yeast to human has blurred the definition and physical boundaries of genes. Using multiple analysis approaches we have characterized individual gene boundaries mapping on human chromosomes 21 and 22. Analyses of the locations of the 5' and 3' transcriptional termini of 492 protein coding genes revealed that for 85% of these genes the boundaries extend beyond the current annotated termini, most often connecting with exons of transcripts from other well annotated genes. The biological and evolutionary importance of these chimeric transcripts is underscored by (1) the non-random interconnections of genes involved, (2) the greater phylogenetic depth of the genes involved in many chimeric interactions, (3) the coordination of the expression of connected genes and (4) the close in vivo and three dimensional proximity of the genomic regions being transcribed and contributing to parts of the chimeric RNAs. The non-random nature of the connection of the genes involved suggest that chimeric transcripts should not be studied in isolation, but together, as an RNA network. This work has been supported by grants U01HG003150 and U01HG003147 from the National Human Genome Research for the ENCODE project. RG was also supported by a grant from the Spanish Ministry of Education and Science. In addition, KS-A, RM, XY, CL, LG and MV were supported by a grant from the Ellison Foundation and as Institute Sponsored Research from the Dana Farber Cancer Institute Strategic Initiative. The laboratories of SA and AR were supported by grants from the Swiss National Science Foundation and the European Commission AnEUploidy Integrated Project. SA was also supported by the National Center of Excellence ‘‘Frontiers in Genetics’’, ChildCare Foundation and an ERC grant from the European Union. AF, TH and JM acknowledge support from the Wellcome Trust. The work of JLG and MO has been supported by the Spanish Ministry of Science (CTQ2005-09365-C02-02, BIO2009-10964), Instituto Nacional de Bioinformática, the Consolider E-science project (CSD2007-00050), COMBIOMED RETICS and the Fundación Marcelino Botin. JD is supported by a grant from the National Institutes of Health (HG003143) and a W. M. Keck Foundation Distinguished Young Scholar Award. JS is supported by a grant from the National Institutes of Health (U54 HG004592). The work of MT and AV was supported by Consolider E-Science (CSD2007-00050) and the Instituto Nacional de Bioinformática. MV (Center for Cancer Systems Biology, CCSB) is a ‘‘Chercheur Qualifié Honoraire’’ from the Fonds de la Recherche Scientifique (FRS-FNRS, French Community of Belgium). This work has also been funded by grant to TG by NHGRI (U54HG004557) and partially byAffymetirix, Corp

Published
2012

21. Landscape of transcription in human cells

Author

Tyler Alioto, Colin Kingswood, Lorian Schaffer, Sylvain Foissac, Kimberly Bell, Diane Trout, Wei Lin, Nathalie Walters, Thomas R. Gingeras, Oscar Junhong Luo, Pedro G. Ferreira, Atif Shahab, Assaf Gordon, Kata Fejes-Toth, Joao Curado, Jacqueline Chrast, Thomas Derrien, Georgi K. Marinov, Hazuki Takahashi, Alexander Dobin, Nadav Bar, Lei-Hoon See, Morgan C. Giddings, Erica Dumais, Michael Sammeth, Philipp Kapranov, Jainab Khatun, Meagan Fastuca, Jørgen Skancke, Ian Bell, Emilie Falconnet, Roderic Guigó, Huaien Wang, Kimberly Persaud, Alexandre Reymond, Carrie A. Davis, Xiaoan Ruan, Rehab F. Abdelhamid, Daniel Robyr, Joel Rozowsky, Ana Maria Suzuki, Sonali Jha, Marion S. Röder, Sudipto K. Chakrabortty, Brian A. Risk, Hagen Tilgner, Eddie Park, Stylianos E. Antonarakis, Piero Carninci, Hui Gao, Sarah Djebali, Timo Lassmann, Andrea Tanzer, Philippe Batut, Cédric Howald, Yanbao Yu, Ali Mortazavi, Felix Kokocinski, Jennifer Harrow, Mark Gerstein, Melissa J. Fullwood, Chenghai Xue, Gregory J. Hannon, Xian Chen, Igor Antoshechkin, Yoshihide Hayashizaki, Brian A. Williams, Chris Zaleski, John A. Wrobel, Radha Duttagupta, Barbara J. Wold, Julien Lagarde, David Gonzalez, Yijun Ruan, Tim Hubbard, Angelika Merkel, Rory Johnson, Jonathan B. Preall, Jorg Drenkow, Brandon King, Paolo Ribeca, Harsha P. Gunawardena, Jacqueline Dumais, Felix Schlesinger, Michael T. Baer, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Universitat Pompeu Fabra [Barcelona] (UPF), Cold Spring Harbor Laboratory, Riken Yokohama Institute, California Institute of Technology (CALTECH), University of California [Irvine] (UCI), University of California, Boise State University, Yale University [New Haven], The Wellcome Trust Sanger Institute [Cambridge], Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), Affymetrix Inc., University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Université de Lausanne (UNIL), Laboratoire de Génétique Cellulaire (LGC), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, University of Geneva [Switzerland], (IGE3 Inst Genet & Genom Geneva), University of Geneva Medical School, Genome Institute of Singapore (GIS), St Laurent Institut, Falconnet, Emilie, Robyr, Daniel, Reymond, Alexandre, Antonarakis, Stylianos, Universitat Pompeu Fabra [Barcelona], Ecole Nationale Vétérinaire de Toulouse (ENVT), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)

Subjects
Encyclopedias as Topic, Repetitive Sequences, Nucleic Acid/genetics, Polyadenylation, [SDV]Life Sciences [q-bio], Genoma humà, Genome, Repetitive Sequences, RNA Editing/genetics, 0302 clinical medicine, Exons/genetics, Protein Isoforms, RNA/biosynthesis/genetics, ddc:576.5, RNA Splicing/genetics, Genetics, 0303 health sciences, Multidisciplinary, Exons, Genomics, Transcriptome/genetics, Long non-coding RNA, Enhancer Elements, Genetic, 030220 oncology & carcinogenesis, Sequence Analysis, Transcription, Human, Enhancer Elements, General Science & Technology, 1.1 Normal biological development and functioning, RNA Splicing, DNA, Intergenic/genetics, Computational biology, DNA/genetics, Biology, Article, Cell Line, 03 medical and health sciences, Genetic, Underpinning research, Protein Isoforms/genetics, map, expression, Humans, Genes/genetics, genome, Gene, Alleles, Transcription, Genetic/genetics, 030304 developmental biology, Intergenic, Nucleic Acid, small rnas, Sequence Analysis, RNA, Gene Expression Profiling, Human Genome, RNA, Molecular Sequence Annotation, DNA, Regulatory Sequences, Nucleic Acid/genetics, Gene expression profiling, Genes, Genome, Human/genetics, Polyadenylation/genetics, RNA/biosynthesis, RNA/genetics, enhancer, identification, Human genome, Generic health relevance, RNA Editing, Transcriptome, Regulatory Sequences, Genètica
Abstract

Eukaryotic cells make many types of primary and processed RNAs that are found either in specific subcellular compartments or throughout the cells. A complete catalogue of these RNAs is not yet available and their characteristic subcellular localizations are also poorly understood. Because RNA represents the direct output of the genetic information encoded by genomes and a significant proportion of a cell's regulatory capabilities are focused on its synthesis, processing, transport, modification and translation, the generation of such a catalogue is crucial for understanding genome function. Here we report evidence that three-quarters of the human genome is capable of being transcribed, as well as observations about the range and levels of expression, localization, processing fates, regulatory regions and modifications of almost all currently annotated and thousands of previously unannotated RNAs. These observations, taken together, prompt a redefinition of the concept of a gene. This work was supported by the National Human Genome Research Institute (NHGRI) production grants U54HG004557, U54HG004555, U54HG004576 and U54HG004558, and by the NHGRI pilot grant R01HG003700. It was also supported by the NHGRI ARRA stimulus grant 1RC2HG005591, the National Science Foundation (SNF) grant 127375, the European Research Council (ERC) grant/n249968, a research grant for the RIKEN Omics Science Center from the Japanese Ministry of Education, Culture, Sports, Science and Technology, and grants BIO2011-26205, CSD2007-00050 and INB GNV-1 from the Spanish Ministry of Science

Published
2012

22. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus

Author

Stephen W. Scherer, Mònica Gratacòs, Kari Stefansson, Muriel Holder, Unnur Thorsteinsdottir, Lukas Forer, Katharina M. Roetzer, Josette Lucas, Claudia Schurmann, Satu Kaksonen, Armand Valsesia, Carina Wallgren-Pettersson, Barbara Leube, Alexandra I. F. Blakemore, Alexandre Moerman, Marco Belfiore, Anne Faudet, Dominique Gaillard, Roberto Ravazzolo, Dominique Bonneau, Marjo-Riitta Järvelin, Yongguo Yu, Louis Vallée, Bénédicte Demeer, Sophie Visvikis-Siest, Frédérique Béna, Brigitte H. W. Faas, Benoit Arveiler, Georg Homuth, Charles Coutton, Bénédicte de Fréminville, Giorgio Gimelli, Xavier Estivill, Richard I. Fisher, Stefania Gimelli, Wendy Roberts, Jacques S. Beckmann, Emilie Landais, Orah S. Platt, Robin G. Walters, Gudmar Thorleifsson, Alexandre Reymond, Anna-Liisa Hartikainen, Solenn Legallic, James F. Gusella, Peter Vollenweider, Gian Paolo Ramelli, Tõnu Esko, Boris Keren, Nine V A M Knoers, Fanny Morice-Picard, Dominique Campion, Odile Boute, Evica Rajcan-Separovic, Rolph Pfundt, Nathalie Bednarek, Martine Doco-Fenzy, Suzanne M E Lewis, Gérard Didelot, Mylène Beri, Engilbert Sigurdsson, Véronique Satre, Audrey Labalme, Carola Tengstrom, Florian Kronenberg, Florence Petit, Simon Zwolinksi, Philippe Froguel, Paul Elliott, Dorothée Cailley, Christian R. Marshall, Bruno Leheup, Klaus Dieterich, Janina S. Ried, Sylvie Jaillard, Armand Bottani, Stylianos E. Antonarakis, Elisabetta Lapi, Jean-Christophe Cuvellier, Robert M. Witwicki, Gérard Waeber, Christèle Dubourg, Marion Gérard, Lachlan J. M. Coin, Magalie Barth, Anita Kloss-Brandstätter, Vincent Mooser, Cristóbal Richart, Giuseppe Merla, Bénédicte Duban-Bedu, Yiping Shen, Ants Kurg, Audrey Guilmatre, Juliane Hoyer, Susana Jiménez-Murcia, Mafalda Mucciolo, Bai-Lin Wu, Alessandra Ferrarini, Séverine Drunat, Yves Alembik, Páll Magnússon, Han G. Brunner, Maria Antonietta Mencarelli, Dominique Descamps, R. Frank Kooy, Azzedine Aboura, Valérie Layet, Sven Bergmann, Thomas Meitinger, Peter M. Kroisel, Nathalie Van der Aa, Olivier Guillin, Michèle Mathieu-Dramard, Zoltán Kutalik, Elisabeth Flori, Laurent Pasquier, André Reis, Noam D. Beckmann, Bertrand Isidor, Delphine Héron, Philippe Jonveaux, Sergi Villatoro Gomez, Ann Nordgren, José Manuel Fernández-Real, Florence Fellmann, Fernando Fernández-Aranda, Laurence Faivre, Dimitri J. Stavropoulos, Katrin Männik, Christian Gieger, Evald Saemundsen, Agnès Guichet, Jean-Marie Cuisset, R. Touraine, Laura Bernardini, Marie-Ange Delrue, Alessandra Renieri, Omar Gustafsson, Flore Zufferey, David A. Koolen, Massimiliano Rossi, Jacqueline Chrast, Ghislaine Plessis, Faida Walha, Joris Andrieux, Ellen van Binsbergen, Albert David, Catherine Vincent-Delorme, Cédric Le Caignec, Jean Chiesa, Ndeye Coumba Ndiaye, Geraldine Joly Helas, Damien Sanlaville, Anita Rauch, Louise Harewood, Mark I. McCarthy, Bridget A. Fernandez, Sébastien Jacquemont, Hreinn Stefansson, Anneke T. Vulto-van Silfhout, Zdenek Jaros, Matthias Nauck, Hans J. Grabe, Sonia Bouquillon, Mieke M. van Haelst, Andres Metspalu, Loyse Hippolyte, Patrick Callier, Bert B.A. de Vries, Francisco J. Tinahones, Nicole de Leeuw, Julia S. El-Sayed Moustafa, Claudine Rieubland, Kay D. MacDermot, Vittoria Disciglio, Henry Völzke, Caroline Rooryck, Bettina Blaumeiser, Danielle Martinet, Marie-Claude Addor, Bruno Delobel, Jacquemont, S, Reymond, A, Zufferey, F, Harewood, L, Walters, Rg, Kutalik, Z, Martinet, D, Shen, Y, Valsesia, A, Beckmann, Nd, Thorleifsson, G, Belfiore, M, Bouquillon, S, Campion, D, de Leeuw, N, de Vries, Bb, Esko, T, Fernandez, Ba, Fernández-Aranda, F, Fernández-Real, Jm, Gratacòs, M, Guilmatre, A, Hoyer, J, Jarvelin, Mr, Kooy, Rf, Kurg, A, Le Caignec, C, Männik, K, Platt, O, Sanlaville, D, Van Haelst, Mm, Villatoro Gomez, S, Walha, F, Wu, Bl, Yu, Y, Aboura, A, Addor, Mc, Alembik, Y, Antonarakis, Se, Arveiler, B, Barth, M, Bednarek, N, Béna, F, Bergmann, S, Beri, M, Bernardini, L, Blaumeiser, B, Bonneau, D, Bottani, A, Boute, O, Brunner, Hg, Cailley, D, Callier, P, Chiesa, J, Chrast, J, Coin, L, Coutton, C, Cuisset, Jm, Cuvellier, Jc, David, A, de Freminville, B, Delobel, B, Delrue, Ma, Demeer, B, Descamps, D, Didelot, G, Dieterich, K, Disciglio, V, Doco-Fenzy, M, Drunat, S, Duban-Bedu, B, Dubourg, C, El-Sayed Moustafa, J, Elliott, P, Faas, Bh, Faivre, L, Faudet, A, Fellmann, F, Ferrarini, A, Fisher, R, Flori, E, Forer, L, Gaillard, D, Gerard, M, Gieger, C, Gimelli, S, Gimelli, G, Grabe, Hj, Guichet, A, Guillin, O, Hartikainen, Al, Heron, D, Hippolyte, L, Holder, M, Homuth, G, Isidor, B, Jaillard, S, Jaros, Z, Jiménez-Murcia, S, Helas, Gj, Jonveaux, P, Kaksonen, S, Keren, B, Kloss-Brandstätter, A, Knoers, Nv, Koolen, Da, Kroisel, Pm, Kronenberg, F, Labalme, A, Landais, E, Lapi, E, Layet, V, Legallic, S, Leheup, B, Leube, B, Lewis, S, Lucas, J, Macdermot, Kd, Magnusson, P, Marshall, C, Mathieu-Dramard, M, Mccarthy, Mi, Meitinger, T, Mencarelli, Ma, Merla, G, Moerman, A, Mooser, V, Morice-Picard, F, Mucciolo, M, Nauck, M, Ndiaye, Nc, Nordgren, A, Pasquier, L, Petit, F, Pfundt, R, Plessis, G, Rajcan-Separovic, E, Ramelli, Gp, Rauch, A, Ravazzolo, R, Reis, A, Renieri, A, Richart, C, Ried, J, Rieubland, C, Roberts, W, Roetzer, Km, Rooryck, C, Rossi, M, Saemundsen, E, Satre, V, Schurmann, C, Sigurdsson, E, Stavropoulos, Dj, Stefansson, H, Tengström, C, Thorsteinsdóttir, U, Tinahones, Fj, Touraine, R, Vallée, L, van Binsbergen, E, Van der Aa, N, Vincent-Delorme, C, Visvikis-Siest, S, Vollenweider, P, Völzke, H, Vulto-van Silfhout, At, Waeber, G, Wallgren-Pettersson, C, Witwicki, Rm, Zwolinksi, S, Andrieux, J, Estivill, X, Gusella, Jf, Gustafsson, O, Metspalu, A, Scherer, Sw, Stefansson, K, Blakemore, Ai, Beckmann, J, Froguel, P, Faculteit Medische Wetenschappen/UMCG, Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Department of Genomics of Common Disease, Imperial College London, Department of Medical Genetics, Université de Lausanne = University of Lausanne (UNIL), Laboratory Medicine, Boston Children's Hospital, Center for Human Genetic Research, Massachusetts General Hospital [Boston], Ludwig Institute for Cancer Research, deCODE Genetics, deCODE genetics [Reykjavik], Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Estonian Genome and Medicine, University of Tartu, Department of human genetics, Radboud University Medical Center [Nijmegen]-Nijmegen Centre for Molecular Life Sciences-Institute for Genetic and Metabolic Disorders, Institute of Molecular and Cell Biology, Disciplines of Genetics and Medicine, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Department of Psychiatry (IDIBELL), CIBERobn Fisiopatología de la Obesidad y Nutrición-University Hospital of Bellvitge, Section of Diabetes, Endocrinology and Nutrition, University Hospital of Girona-Biomedical Research Institute 'Dr Josep Trueta'-CIBERobn Fisiopatología de la Obesidad y Nutrición, Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Department of child and adolescent health, University of Oulu-Institute of Health Sciences and Biocenter Oulu-National Institute for Health and Welfare [Helsinki], Antwerp University Hospital [Edegem] (UZA), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, University Medical Center [Utrecht], Institutes of Biomedical Science, Fudan University [Shanghai]-Children's Hospital, Shanghai Children's Medical Center, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de cytogénétique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Génétique médicale, Hôpitaux Universitaires de Genève (HUG), Maladies Rares - Génétique et Métabolisme (MRGM), Université Bordeaux Segalen - Bordeaux 2-Hôpital Pellegrin-Service de Génétique Médicale du CHU de Bordeaux, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université de Reims Champagne-Ardenne (URCA), Department of Molecular Genetics, Weizmann Institute of Science [Rehovot, Israël], Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Service de Génétique clinique, Laboratoire de cytogénétique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Cytogénétique, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-faculté de médecine-pharmacie, AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Service de Neuropédiatrie, Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), CHU Amiens-Picardie, Centre Hospitalier de Béthune (CH Béthune), GHT de l'Artois, Service de Génétique Clinique, Department of Biotechnology, Università degli Studi di Siena = University of Siena (UNISI)-Medical Genetics, Service de Génétique, Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Maison Blanche-IFR 53, Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Department of Epidemiology and Public Health, Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Department of Experimental Cardiology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Heart Failure Research Center (HFRC), CHU Pitié-Salpêtrière [AP-HP], Institute of human genetics, International Centre for Life, Division of genetic epidemiology, HMNC Brain Health-Molecular and Clinical Pharmacology-Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Department of Obstetrics and Gynecology, University of Oulu-Institute of Clinical Medicine, Laboratorio di citogenetica, G. Gaslini Institute, Department of Psychiatry and Psychotherapy, Universität Greifswald - University of Greifswald, Interfaculty Institute for Genetics and Functional Genomics, Abteilung für Kinder und Jugendheilkunde, Landesklinikum Waldviertel Zwettl, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), The Habilitation Unit of Folkhalsan, Medical University Graz, Medical Genetics Unit, Children's Hospital Anna Meyer, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Institute of Human Genetics and Anthropology, Heinrich-Heine University Hospital Duesseldorf, Child and Family Research Institute-University of British Columbia (UBC), North West Thames Regional Genetics Service, Northwick Park & St Marks Hospital, Child and Adolescent Psychiatry, Landspitali University Hospital, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, The Wellcome Trust Centre for Human Genetics [Oxford], Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Genetics, GlaxoSmithKline R&D, GlaxoSmithKline, Institute of Clinical Chemistry and Laboratory Medicine, Génétique cardiovasculaire (GC), Université Henri Poincaré - Nancy 1 (UHP), Molecular Medicine and Surgery department, Karolinska Institutet [Stockholm], Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Pathology, Division of pediatrics, Ospedale San Giovanni, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Department of pediatrics and CEBR, Università degli studi di Genova = University of Genoa (UniGe)-G. Gaslini Institute, Department of Internal Medicine, Universitat Rovira i Virgili-University Hospital Juan XXIII-Instituto Salud Carlos III-Ciber Fisiopatologia Obesidad y Nutricion (CIBEROBN), Division of Human Genetics, Department of Paediatrics, Inselspital-University of Bern, Autism Research Unit, The Hospital for sick children [Toronto] (SickKids)-University of Toronto, State Diagnostic, Counseling Center, University of Iceland [Reykjavik], Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Genetic Services, Rinnekoti Research Foundation, Department of Endocrinology and Nutrition, Instituto Salud Carlos III-Clinic Hospital of Virgen de la Victoria-Ciber Fisiopatologia y Nutricion (CIBEROBN), Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, Institute for Community Medicine, Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Institut de biologie de Lille - UMS 3702 (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Leenaards Foundation Prize (SJ, DM and AR), the Jérôme Lejeune Foundation (AR), the Telethon Action Suisse Foundation (AR), the Swiss National Science Foundation (AR, JSB, SB and SEA), a SNSF Sinergia grant (SJ, DM, SB, JSB and AR), the European Commission anEUploidy Integrated Project grant 037627 (AR, SB, XE, HGB and SEA), the Ludwig Institute for Cancer Research (AV), the Swiss Institute of Bioinformatics (SB, ZK), an Imperial College Dept of Medicine PhD studentship (JSe-SM), the Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust, and the National Institute for Health Research (PE), the Wellcome Trust and the Medical Research Council (AIFB and PF), the Instituto de Salud Carlos III (ISCIII)-FIS, the German Mental Retardation Network funded through a grant of the German Federal Ministry of Education and Research (NGFNplus 01GS08160) to A Reis and European Union-FEDER (PI081714, PS09/01778), SAF2008-02278 (XE, MG, FFA), the Belgian National Fund for Scientific Research - Flanders (NVA, RFK), the Dutch Organisation for Health Research and Development (ZONMW grant 917-86-319) and Hersenstichting Nederland (BBAdV), grant 81000346 from the Chinese National Natural Science Foundation (YGY), the Simons Foundation Autism Research Initiative, Autism Speaks and NIH grant GM061354 (JFG), and the OENB grant 13059 (AK-B). YS holds a Young Investigator Award from the Children's Tumor Foundation and Catalyst Award from Harvard Medical School, and BLW, a Fudan Scholar Research Award from Fudan University, a grant from Chinese National '973' project on Population and Health (2010CB529601) and a grant from Science and Technology Council of Shanghai (09JC1402400). ERS and SL, recipients of the Michael Smith Foundation for Health Research Scholar award, acknowledge the CIHR MOP 74502 operational grant. EGCUT received support from the EU Centre of Excellence in Genomics and FP7 grants #201413 and #245536, from Estonian Government SF0180142s08, SF0180026s09 and SF0180027s10 (AM, KM, AK). The Helmholtz Zentrum Munich and the State of Bavaria financed KORA, also supported by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823), the German Federal Ministry of Education and Research (BMBF), and the Munich Center of Health Sciences (MC Health, LMUinnovativ). CIBEROBN and CIBERESP are initiatives of ISCIII (Spain). SWS holds the GlaxoSmithKline-Canadian Institutes of Health (CIHR) Chair in Genetics, Genomics at the University of Toronto and the Hospital for Sick Children and is supported by Genome Canada and the McLaughlin Centre. deCODE was funded in part by NIH grant MH071425 (KS), EU grant HEALTH-2007-2.2.1-10-223423 (Project PsychCNV) and EU grant IMI-JU-NewMeds., Centre de génomique intégrative, Université de Lausanne (UNIL), Swiss Institute of Bioinformatics (SIB), Swiss Institute of Bioinformatics, Memorial University of Newfoundland [St. John's], Friedrich Alexander University [Erlangen-Nürnberg], Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Weizmann Institute of Science, IRCCS Casa Sollievo della Sofferenza Hospital, Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Saint-Etienne-Hôpital nord, Hôpital Saint Vincent de Paul-GHICL, Centre hospitalier de Béthune, Università degli Studi di Siena (UNISI)-Medical Genetics, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Innsbruck Medical University [Austria] (IMU)-HMNC Brain Health-Molecular and Clinical Pharmacology, Czech Academy of Sciences [Prague] (ASCR), University of Oxford [Oxford], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, University of Zürich [Zürich] (UZH), Universita degli studi di Genova -G. Gaslini Institute, University of Toronto-The Hospital for Sick Children, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), De Villemeur, Hervé, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland., Other departments, Reymond, Alexandre, Antonarakis, Stylianos, Sloan Bena, Frédérique, Bottani, Armand, Callier, Patrick, Gimelli, Stefania, Merla, Giuseppe, Vollenweider, Peter, Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Université de Lille-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Aging, Transcription, Genetic, Adolescent, Adult, Aged, Body Height, Body Mass Index, Case-Control Studies, Child, Child, Preschool, Chromosomes, Human, Pair 16, Cohort Studies, Comparative Genomic Hybridization, Developmental Disabilities, Energy Metabolism, Europe, Female, Gene Dosage, Gene Duplication, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Head, Heterozygote, Humans, Infant, Infant, Newborn, Mental Disorders, Middle Aged, Mutation, North America, Obesity, Phenotype, RNA, Messenger, Sequence Deletion, Thinness, Young Adult, Physiology, RNA, Messenger/analysis/genetics, Genome-wide association study, HIDDEN-MARKOV MODEL, 0302 clinical medicine, Sequence Deletion/genetics, ddc:576.5, 0303 health sciences, education.field_of_study, Body Height/genetics, Genetic Predisposition to Disease/genetics, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, population characteristics, Chromosomes, Human, Pair 16/genetics, Human, Locus (genetics), Gene Duplication/genetics, Article, 03 medical and health sciences, Genetic, education, SNP GENOTYPING DATA, Thinness/genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Pair 16, Case-control study, nutritional and metabolic diseases, social sciences, medicine.disease, DEPENDENT PROBE AMPLIFICATION, Human medicine, Body mass index, 030217 neurology & neurosurgery, Messenger, Obesity/genetics, FAILURE-TO-THRIVE, [SDV.GEN] Life Sciences [q-bio]/Genetics, Head/anatomy & histology, METABOLIC SYNDROME, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 2. Zero hunger, Genetics, Multidisciplinary, TIME QUANTITATIVE PCR, Failure to thrive, medicine.symptom, Underweight, Transcription, geographic locations, Mutation/genetics, Population, Biology, Chromosomes, 150 000 MR Techniques in Brain Function, medicine, Preschool, 030304 developmental biology, COPY NUMBER VARIATION, Mental Disorders/genetics, Energy Metabolism/genetics, RELATIVE QUANTIFICATION, Gene Dosage/genetics, Newborn, BODY-MASS INDEX, CIRCULAR BINARY SEGMENTATION, RNA, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], human activities, Developmental Disabilities/genetics
Abstract

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance. Leenaards Foundation Jerome Lejeune Foundation Telethon Action Suisse Foundation Swiss National Science Foundation European Commission 037627 QLG1-CT-2000-01643 Ludwig Institute for Cancer Research Swiss Institute of Bioinformatics Imperial College Department of Medicine Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust National Institute for Health Research Wellcome Trust Medical Research Council Instituto de Salud Carlos III (ISCIII)-FIS German Mental Retardation Network German Federal Ministry of Education and Research NGFNplus 01GS08160 European Union PI081714 PS09/01778 201413 245536 info:eu-repo/grantAgreement/EC/FP7/223423 Belgian National Fund for Scientific Research, Flanders Dutch Organisation for Health Research and Development (ZON-MW) 917-86-319 Hersenstichting Nederland (B.B.A.d.V.) Chinese National Natural Science Foundation 81000346 Simons Foundation Autism Research Initiative Autism Speaks NIH GM061354 MH071425 Oesterreichische Nationalbank (OENB) 13059 Children's Tumor Foundation Harvard Medical School Fudan University Chinese National '973' project on Population and Health 2010CB529601 Science and Technology Council of Shanghai 09JC1402400 Michael Smith Foundation for Health CIHR MOP 74502 Estonian Government SF0180142s08 SF0180026s09 SF0180027s10 Helmholtz Zentrum Munich State of Bavaria German National Genome Research Network 01GS0823 German Federal Ministry of Education and Research (BMBF) Munich Center of Health Sciences (MC Health, LMUinnovativ) Genome Canada McLaughlin Centre Academy of Finland 104781 120315 129269 1114194 University Hospital Oulu Biocenter University of Oulu, Finland 75617 NHLBI 5R01HL087679-02 1RL1MH083268-01 NIH/NIMH 5R01MH63706:02 ENGAGE project Medical Research Council, UK G0500539 G0600705 Academy of Finland Biocentrum Helsinki SAF2008-02278 HEALTH-F4-2007-201413

Published
2011

23. The genome sequence of taurine cattle: A window to ruminant biology and evolution

Author

Heather M Deobald, Gerald R. Fowler, Clay Davis, Judith Herdandez, Donna Maglott, Lin Chen, Gonzalo Rincon, Darren E. Hagen, James T. Warren, Evgenia V. Kriventseva, Ingrid Olsaker, Debora L. Hamernik, Charles Moen, Oliver C. Jann, Yuri Kapustin, Erdogan Memili, Timothy Connelley, Ling Ling Pu, Terhi Iso-Touru, Gemma Marie Payne, Ye Cheng, Amy Egan, Alexandre Reymond, Aniko Sabo, J. Bruce German, Jason R. Grant, Joseph Chacko, Ronnie D. Green, Isabel Kinney Ferreira de Miranda Santos, Raffaele Mazza, A.J. Molenaar, Richard A. Moore, Christian J. Buhay, Henry Song, Cham G. Kumar, Marion L. Greaser, Hasan Khatib, Harris A. Lewin, Olga Ermolaeva, Jonathan V. Sweedler, Steven J.M. Jones, Rosemeire Conceição Parra Pastor, Paul Stothard, Adam J. Colley, Antti Livanainen, Francesca Panzitta, Dan Graur, Aaron Ingham, David L. Adelson, Timothy P. L. Smith, Shirley A. Ellis, Andy Cree, Jingkun Zhang, Carolyn T.A. Herzig, Jason Goodell, Colette A. Abbey, Feng-Qi Zhao, Mimi M. Chandrabose, Ross L. Tellam, Alex Astashyn, Yanru Ren, Laura Elnitski, Bella Mayurkumar Patel, Sem Genini, Lassudara G. Almeida, Jacqueline E. Schein, Theresa Casey, Hanni Salih, José Fernando Garcia, Zhiquan Wang, Carolyn Fitzsimmons, Evan E. Eichler, Ngoc Nguyen, Kaitlin E. Donohue, Ariel Fernando Amadio, Clayton R. Boldt, John C. McEwan, Juan Manuel Anzola, Francisco Câmara, Shoba Ranganathan, Eran Elhaik, Stefan Hiendleder, George M. Weinstock, Lora Lewis, Jeremy F. Taylor, Dimos Kapetis, Andrew J. Roberts, Lee Alexander, Nelida Rodriguez-Osorio, Alexandre Souvorov, Justin C. Lee, Bruce R. Southey, Boris Kiryutin, Michael Holder, Xiang Qin, Warren M. Snelling, Abhirami Ratnakumar, Marcelo Fábio Gouveia Nogueira, Angela K. Walker, Hatam A. Hakimov, Fernando H. Biase, Roderic Guigó, Shannon Dugan-Rocha, Sean McWilliam, Rex Lee Williams, Jacqueline Chrast, Huyen Dinh, Robert C. Edgar, Huaiyang Jiang, Justin T. Reese, John W. Keele, George E. Liu, Yufeng Shen, Jireh Santibanez, Kim C. Worley, Sandra L. Lee, Sari S. Khalil, Marta Hernández, Stephen N. White, Suria M. Bahadue, Changxi Li, Kim D. Pruitt, Kirsty Jensen, C. Michael Dickens, Jung-Woo Choi, Jennifer Harrow, Tatiana A. DeCampos, Richard A. Gibbs, Ryan J. Lozado, Yoshikazu Sugimoto, Sigbjam Lien, Anna K. Bennett, Curtis P. Van Tassell, Eve Devinoy, Gustavo Garcia, R. Baxter, Satyanarayana Rachagani, Kevin K. Lahmers, Stylianos E. Antonarakis, D. Kolbehdari, Cynthia L. Baldwin, Lillian Sando, Darryl L. Hadsell, Elen Anatriello, Ze Cheng, Richard C. Waterman, Paul Havlak, Peter Dove, Laura Sherman, Wes Barris, Imke Tammen, Geoffrey Okwuonu, Jennifer Hume, Denis M. Larkin, Robert D. Schnabel, Zhi-Liang Hu, Evgeny M. Zdobnov, Danielle G. Lemay, Stephanie Bell, Roberto Malinverni, Jiuzhou Song, David Steffen, James M. Reecy, Lynne V. Nazareth, Carlo José Freire de Oliveira, E. Marques, Cody J. Gladney, Donna M. Muzny, Candice L. Brinkmeyer-Larigford, Lakshmi K. Matukumalli, Jan Aerts, Stephen S. Moore, Margaret Morgan, Kim L. McLean, Juan F. Medrano, Felix Kokocinski, Marco A. Marra, Gregory P. Harhay, Frank W. Nicholas, Loren C. Skow, Fiona S. L. Brinkman, Tovah Kerr, Krista L. Fritz, Stacey M. Curry, Charlotte N. Henrichsen, Catherine Ucla, David J. Lynn, Victor V. Solovyev, Natasha E. Romero, Sandra Hines, Joy M. Raison, Alessandra Mara Franzin, Selina Vattathil, Jeffery A. Carroll, Brian P. Dalrymple, Katarzyna Wilczek-Boney, Seongwon Seo, Richard J. Leach, Mireya Plass, Paul Kitts, Kris R. Wunderlich, Bhanu Prakash V.L. Telugu, Gary L. Bennett, Ramatu Ayiesha Gabisi, Ravikiran Donthu, Shalini N. Jhangiani, Rita A. Wright, Mary Qu Yang, Nauman J. Maqbool, W. A. Carvalho, Monique Rijnkels, Yuri Tani Utsunomiya, Charles E. Chappie, John L. Williams, Rob Halgren, Stephen M. J. Searle, A.R.R. Abatepaulo, Thomas Junier, Stephanie D. McKay, Anne G. Rosenwald, David A. Wheeler, Rosemarie Weikard, N. Hastings, Roger T. Stone, Eduardo Eyras, Cerissa Hamilton, Wendy C. Brown, Yan Ding, Ylva Strandberg Lutzow, Matthew Hobbs, Annett Eberlein, Carine Wyss, Jennifer M. Urbanski, Matthew Peter Kent, Lilian P.L. Lau, Dinesh Kumar, Penny K. Riggs, Lawrence B. Schook, Matthew Hitchens, Vandita Joshi, Melissa J. Landrum, Tyler Alioto, Nathan Poslusny, Thomas T. Wheeler, Victor Sapojnikov, Natália F. Martins, San Juana Ruiz, Michael D. MacNeil, Alexandre Rodrigues Caetano, Mario Andres Poli, Catherine Jamis, Masaaki Taniguchi, James E. Womack, William F. Martin, Andrej Razpet, James G. R. Gilbert, Daniel G. Bradley, Readman Chiu, Thomas H. Welsh, Clare A. Gill, Erica Sodergren, Carol G. Chitko-McKown, Hari Prasad Nandakumar, Virpi Ahola, Steve M. Kappes, Jennifer E. Chapin, Sandra Regina Maruyama, John Lopez, Krystin M. Logan, Jonathan A. Green, Laurens G. Wilming, Yue Liu, Antti Iivanainen, Robert A. Holt, Barbara T. Moreno, Marcos De Donato, Christie Kovar, Angela Jolivet Johnson, Carl T. Muntean, Robert Ward, K. James Durbin, Matthew D. Whiteside, Christopher P. Childers, Tad S. Sonstegard, Yin Shin Liu, Bin Zhu, Sameer D. Pant, Ashley J. Waardenberg, André Eggen, D.M. Spurlock, Hsiu Chuan Chen, Le Luo Guan, Sandra L. Rodriguez-Zas, Akiko Takasuga, Daniela D. Moré, Jianqi Yang, Wratko Hlavina, Sheila M. Schmutz, Michael J. Brownstein, Christine G. Elsik, Marvin Diep Dao, Daniel Gerlach, E. Hart, Elsa Chacko, Elizabeth Glass, Libing Shen, Chris P. Verschoor, Eliane P. Cervelatti, Department of Biology, Georgetown University, Department of Animal Science, Texas A&M University [College Station], Livestock Industries, Baylor College of Medicine (BCM), Reymond, Alexandre, Zdobnov, Evgeny, Antonarakis, Stylianos, Ucla, Catherine, Gerlach, Daniel, and Junier, Thomas

Subjects
Male, genome sequence, [SDV]Life Sciences [q-bio], ved/biology.organism_classification_rank.species, Genome, Genética y Herencia, Segmental duplication, 2. Zero hunger, Genetics, ddc:616, 0303 health sciences, Multidisciplinary, 04 agricultural and veterinary sciences, Bovine genome, Animals, Domestic, Proteins/genetics, Female, CIENCIAS NATURALES Y EXACTAS, Sequence analysis, Evolution, Biotecnología Agropecuaria, Molecular Sequence Data, Tecnología GM, clonación de ganado, selección asistida, diagnósticos, tecnología de producción de biomasa, etc, Biology, Synteny, Article, Ciencias Biológicas, Evolution, Molecular, 03 medical and health sciences, Species Specificity, Animals, Humans, General, Gene, 030304 developmental biology, Whole genome sequencing, ved/biology, Taurine cattle, 0402 animal and dairy science, Genetic Variation, Sequence Analysis, DNA, 040201 dairy & animal science, Bos taurus, Alternative Splicing, MicroRNAs/genetics, CIENCIAS AGRÍCOLAS, cattle, Cattle, genetic
Abstract

To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production. Fil: Bovine Genome Sequencing and Analysis Consortium. Bovine Genome Sequencing And Analysis Consortium; Estados Unidos Fil: Amadio, Ariel Fernando. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Santa Fe. Estación Experimental Agropecuaria Rafaela; Argentina Fil: Poli, Mario Andres. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Genética; Argentina

Published
2009

24. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project

Author

Nan Jiang, Alfonso Valencia, Rachel A. Harte, Abigail Woodroffe, Michael Seringhaus, Andrew Haydock, Eugene Davydov, Todd M. Lowe, Peggy J. Farnham, Robert E. Thurman, Tyler Alioto, Adam Ameur, Morgan Park, Roderic Guigó, Archana Thakkapallayil, Philipp Kapranov, Francis S. Collins, Donna Karolchik, Stefan Washietl, Kerstin Lindblad-Toh, Michael L. Tress, Barbara E. Stranger, Gregory M. Cooper, Kun Wang, Thomas R. Gingeras, Serafim Batzoglou, Peter D. Ellis, Annie Yang, Stylianos E. Antonarakis, Jonghwan Kim, Robert M. Andrews, W. James Kent, Kuo Ping Chiu, Madhavan Ganesh, Jason D. Lieb, Shane Neph, Albin Sandelin, Michael Hawrylycz, Eric S. Lander, Matthew T. Weirauch, Nick Goldman, Alexander E. Urban, Ian Bell, Anason S. Halees, Jan Komorowski, Webb Miller, Kandhadayar G. Srinivasan, Evelyn Cheung, David B. Jaffe, Peter J. Good, Gregory Lefebvre, Yuko Yoshinaga, Sylvain Foissac, Alexander W. Bruce, Mark Dickson, Christoph M. Koch, Antigone S. Dimas, Zhengdong D. Zhang, Matthew J. Oberley, Paul I.W. de Bakker, Arend Sidow, Xueqing Zhang, Molly Weaver, Jane Rogers, Jacquelyn R. Idol, Jeff Goldy, Haiyan Huang, William Stafford Noble, Angie S. Hinrichs, Sandeep Patel, David A. Nix, Lluís Armengol, Siew Woh Choo, Hong Sain Ooi, Sara Van Calcar, Ivan Adzhubei, Job Dekker, Sara J. Cooper, Hari Tammana, Valerie Maduro, Jason A. Greenbaum, Bing Ren, Sharon L. Squazzo, Jennifer C. McDowell, Chikatoshi Kai, Ivo L. Hofacker, Ian Dunham, Peter J. Bickel, Nancy Holroyd, Eduardo Eyras, Julien Lagarde, Fei Yao, Man Yu, Piero Carninci, Chia-Lin Wei, Alice C. Young, Yong Yu, Daryl J. Thomas, George Asimenos, Xiaoqin Xu, Galt P. Barber, Andrea Tanzer, Juan I. Montoya-Burgos, Sujit Dike, Nathan Day, Gregory E. Crawford, Michele Clamp, Todd Richmond, Nuria Lopez-Bigas, Vishwanath R. Iyer, Ewan Birney, Richard Humbert, Gary C. Hon, David Swarbreck, Xiaobin Guan, Sarah Wilcox, Nate Heintzman, Josep F. Abril, Elaine R. Mardis, Stefan Enroth, Charlie W.H. Lee, Nicholas Matthews, Benedict Paten, Robert Castelo, Michael A. Singer, Mousheng Xu, Chiou Yu Choo, Nancy F. Hansen, Elizabeth Rosenzweig, Patrick A. Navas, Jacqueline Chrast, Brett E. Johnson, Jan O. Korbel, Simon Whelan, Stephen Hartman, Ulas Karaoz, Ingileif B. Hallgrímsdóttir, David Haussler, Michael R. Brent, Jill Cheng, Gonçalo R. Abecasis, Ann S. Zweig, Sherman M. Weissman, Michael O. Dorschner, Jin Lian, Vinsensius B. Vega, Cordelia Langford, Alexandre Reymond, Mark Gerstein, Pawandeep Dhami, Ola Wallerman, Huaiyang Jiang, Lior Pachter, James Taylor, Eric A. Stone, David R. Inman, Yijun Ruan, Peter E. Newburger, Roland Green, Ari Löytynoja, Shelley Force Aldred, Alvaro Rada-Iglesias, Baishali Maskeri, Joel Rozowsky, Jorg Drenkow, Colin N. Dewey, Srinka Ghosh, Yutao Fu, Kayla E. Smith, Xavier Estivill, Donna M. Muzny, Christine P. Bird, Tim Hubbard, Jana Hertel, Kristin Missal, Neerja Karnani, Ericka M. Johnson, Nan Zhang, Zhou Zhu, Stephen C. J. Parker, Minmei Hou, Charlotte N. Henrichsen, Heather A. Hirsch, Caroline Manzano, Laura A. Liefer, Kim C. Worley, Robert Baertsch, Mark S. Guyer, Ross C. Hardison, Zheng Lian, Hiram Clawson, Leah O. Barrera, Manja Lindemeyer, James Cuff, Chunxu Qu, Jun Kawai, Jennifer Hillman-Jackson, Eric D. Green, Robert W. Blakesley, Abel Ureta-Vidal, Rhona K. Stuart, Fabio Pardi, Peter J. Sabo, Edward A. Sekinger, John S. Mattick, Ankit Malhotra, Taane G. Clark, James G. R. Gilbert, James C. Mullikin, Deyou Zheng, Robert M. Kuhn, Tae Hoon Kim, M. Geoff Rosenfeld, Kirsten Lee, Jörg Hackermüller, Oliver M. Dovey, Deanna M. Church, Kyle J. Munn, Peter F. Stadler, Phillippe Couttet, Claudia Fried, Jaafar N. Haidar, Kris A. Wetterstrand, Wing-Kin Sung, Paul G. Giresi, Jia Qian Wu, Ruth Taylor, David A. Wheeler, Zarmik Moqtaderi, Adam Siepel, Michael Snyder, Ian Holmes, Jun Liu, Olof Emanuelsson, Kevin Struhl, Saurabh Asthana, Akshay Bhinge, Adam Frankish, Yoshihide Hayashizaki, Ghia Euskirchen, Joel D. Martin, Robert S. Fulton, Ugrappa Nagalakshmi, Heike Fiegler, Gayle K. Clelland, Shane C. Dillon, Fidencio Neri, Elliott H. Margulies, Sean Davis, Mark Bieda, Tristan Frum, Michael S. Kuehn, Heather Trumbower, Pamela J. Thomas, Kazutoyo Osoegawa, Richard A. Gibbs, Emmanouil T. Dermitzakis, Julian L. Huppert, Richard K. Wilson, Tina Graves, Zhiping Weng, Anthony Shafer, Baoli Zhu, Christopher K. Glass, Patrick J. Boyle, Hennady P. Shulha, Maxim Koriabine, Christoph Flamm, David Vetrie, Nigel P. Carter, Patrick Ng, Peter Kraus, John A. Stamatoyannopoulos, George M. Weinstock, Tim Massingham, Jane M. Lin, Damian Keefe, Jean L. Chang, Shamil R. Sunyaev, Sergey Nikolaev, Kate R. Rosenbloom, Carine Wyss, Hua Cao, Keith D. James, Michael C. Zody, Gerard G. Bouffard, Atif Shahab, Nathan D. Trinklein, James B. Brown, Erica Sodergren, Xiaodong Zhao, Rosa Luna, Sante Gnerre, Paul Flicek, Joanna C. Fowler, Andrew D. Kern, Jakob Skou Pedersen, David C. King, Anindya Dutta, Elise A. Feingold, Richard M. Myers, Richard Sandstrom, Catherine Ucla, Thomas D. Tullius, Mikhail Nefedov, Claes Wadelius, Jennifer Harrow, Christopher M. Taylor, Xiaoling Zhang, Pieter J. de Jong, Dermitzakis, Emmanouil, and Reymond, Alexandre

Subjects
DNA Replication, RNA, Messenger/genetics, Chromatin Immunoprecipitation, Heterozygote, RNA, Untranslated, Transcription, Genetic, Systems biology, Histones/metabolism, RNA, Untranslated/genetics, Pilot Projects, Genomics, Computational biology, Regulatory Sequences, Nucleic Acid, Biology, ENCODE, Genome, Article, DNase-Seq, Histones, Evolution, Molecular, Exons/genetics, Humans, ddc:576.5, Transcription Factors/metabolism, RNA, Messenger, Conserved Sequence, Chromatin/genetics/metabolism, Genetics, Transcription, Genetic/ genetics, Multidisciplinary, Genome, Human, GENCODE, Genetic Variation, Exons, Chromatin, Genetic Variation/genetics, Regulatory Sequences, Nucleic Acid/ genetics, Human genome, Conserved Sequence/genetics, Transcription Initiation Site, Functional genomics, Genome, Human/ genetics, Transcription Factors, Protein Binding
Abstract

We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view about chromatin structure has emerged, including its interrelationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded novel mechanistic and evolutionary insights about the functional landscape of the human genome. Together, these studies are defining a path forward to pursue a more-comprehensive characterisation of human genome function.

Published
2007

25. Mlx, a new Max-like bHLHZip family member: The center stage of a novel transcription factors regulatory pathway?

Author

Silvia Messali, Stefano Cairo, Andrea Ballabio, Giuseppe Merla, Alexandre Reymond, Germana Meroni, Roger Brent, Meroni, G, Cairo, S, Merla, G, Messali, S, Brent, R, Ballabio, Andrea, Reymond, A., Meroni, Germana, Cairo, Stefano, Merla, Giuseppe, Messali, Silvia, Brent, Roger, and Reymond, Alexandre

Subjects
Cancer Research, DNA, Complementary, Molecular Sequence Data, Gene Expression, Myc, Protein Max, Biology, Proto-Oncogene Mas, NO, bHLHZip, Transcription (biology), Genetics, Animals, Humans, Protein Isoforms, Amino Acid Sequence, Genes, Suppressor, Carbohydrate-responsive element-binding protein, MLX, Molecular Biology, Gene, Transcription factor, Cell proliferation, Cell Line, Transformed, Leucine Zippers, Base Sequence, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Helix-Loop-Helix Motifs, Nuclear Proteins, DNA, Max, Rox, DNA-Binding Proteins, Repressor Proteins, Basic-Leucine Zipper Transcription Factors, Histone, bHLHZip, Myc, Max, Rox, cell proliferation, COS Cells, biology.protein, Rabbits, Dimerization, Corepressor, HeLa Cells, Signal Transduction, Subcellular Fractions, Transcription Factors
Abstract

The Myc proto-oncogene family members have been identified as the cellular homologs of the transforming oncogene of avian retroviruses. They encode central regulators of mammalian cell proliferation and apoptosis, and they associate with the bHLHZip protein Max to bind specific DNA sequences and regulate the expression of genes important for cell cycle progression. The other family members, Mad1, Mxi1, Mad3, Mad4 and Rox (Mnt) antagonize their activities. The Mads and Rox compete with Myc in heterodimerizing with Max and in binding to the same specific target sequences. These Mads:Max and Rox:Max dimers repress transcription through binding to the mSIN3 corepressor protein and by tethering histone deacetylase-containing complexes to the DNA. In a screen for Rox interactors we isolated Mlx, a bHLHZip protein previously identified in a screen for Mad1 interactors. In the present work we extend the known dimerization partners of Mlx by demonstrating its ability to interact with Rox. Moreover, we show that contrary to previous reports Mlx is able to homodimerize and to bind E-box sequences at low concentration levels. The possible role of Mlx in an emerging regulatory pathway and acting parallel to the Max driven network is discussed.

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